| 1 | Dan Med Bull 2000 Jun 47: 151-67 |
|---|---|
| PMID | 10913983 |
| Title | Novel pharmacological approaches to the treatment of schizophrenia. |
| Abstract | schizophrenia is a devastating mental disease that affects the human population worldwide with an incidence of about 1%. Over the last decades basic and clinical research has considerably increased our understanding of the pathophysiology of schizophrenia, as well as the mechanism of action of antipsychotic compounds (neuroleptics), and new atypical neuroleptics with equipotent or improved antipsychotic effects and fewer motoric side effects have been developed. However, the pharmacological intervention does not effectively treat all the symptoms of the disease, and there is still a need for new, more effective antipsychotic compounds. Studies of brain function have demonstrated a reduced activation of prefrontal cortical areas during cognitive tasks in schizophrenics. It is hypothesized, that this hypofrontality is associated with a reduced dopaminergic tonus in the prefrontal cortex, which subsequently causes the negative symptoms of schizophrenia, such as apathy and social withdraw. It has also been suggested, that increased dopaminergic activity in striatal areas is related to the wellknown positive schizophrenic symptoms, such as delusions and hallucinations. The present thesis addresses the regional effects of prototypical and atypical neuroleptics on nerve cell activity and dopaminergic tonus in three rat brain areas with special relevance for the pharmacological effects of neuroleptics. Finally, new pharmacological approaches to the medical treatment of schizophrenia are suggested based on our experimental results. Initially, the effects of the prototypical neuroleptic haloperidol and the atypical neuroleptic clozapine on nerve cell activity in the rat forebrain were investigated by measuring the regional expression of the FOS protein. The FOS protein is regarded as a marker of cellular activity and was measured by use of immunohistochemical techniques i) in the medial prefrontal cortex (PFC), probably involved in the negative symptoms of schizophrenia, ii) in the nucleus accumbens (NAc), probably involved in the positive symptoms of schizophrenia and iii) in the dorsolateral striatum (DLSt), most likely involved in the motoric side effects of neuroleptics. Clozapine increases FOS protein immunoreactivity in the PFC with no or minimal effects in the DLSt. In contrast, haloperidol increases FOS protein immunoreactivity in the DLSt with minor effect in the PFC. Other atypical neuroleptics (risperidone, sertindole and NNC 22-0031) induced a FOS protein expression pattern different from haloperidol: The atypical compounds exhibit a larger ratio between FOS protein expression in PFC and DLSt than measured for haloperidol. These results are in accordance with the reported beneficial effects of clozapine, risperidone and sertindole on negative symptoms of schizophrenia and their lower degree of motoric side effects compared to haloperidol. All neuroleptics induced FOS protein immunoreactivity in the NAc, in accordance with their ability to reduce positive psychotic symptoms in schizophrenics. The microdialysis technique was used to investigate the regional dopaminergic effects of the above mentioned antipsychotic compounds by measuring interstitial levels of the dopamine metabolite dihydroxyphenylacetic acid ([DOPAC]i) in PFC, NAc and DLSt. All antipsychotics tested increased [DOPAC]i in the NAc, whereas the atypical antipsychotics clozapine, risperidone, sertindole and NNC 22-0031--in contrast to haloperidol--preferentially increased [DOPAC]i in PFC compared to DLSt. Also these results are in concordance with the clinical effects of clozapine, risperidone, sertindole and haloperidol and support the hypothesis that reduced dopaminergic tone in the prefrontal cortex relates to the negative symptoms of schizophrenia. All clinically efficacious neuroleptics block central dopamine D2 receptors, which include the dopamine D2, D3 and D4 receptor subtypes. The present thesis characterizes a dopamine D3 receptor agonist, cis-OH-PBZI. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 2 | Dan Med Bull 2000 Jun 47: 151-67 |
| PMID | 10913983 |
| Title | Novel pharmacological approaches to the treatment of schizophrenia. |
| Abstract | schizophrenia is a devastating mental disease that affects the human population worldwide with an incidence of about 1%. Over the last decades basic and clinical research has considerably increased our understanding of the pathophysiology of schizophrenia, as well as the mechanism of action of antipsychotic compounds (neuroleptics), and new atypical neuroleptics with equipotent or improved antipsychotic effects and fewer motoric side effects have been developed. However, the pharmacological intervention does not effectively treat all the symptoms of the disease, and there is still a need for new, more effective antipsychotic compounds. Studies of brain function have demonstrated a reduced activation of prefrontal cortical areas during cognitive tasks in schizophrenics. It is hypothesized, that this hypofrontality is associated with a reduced dopaminergic tonus in the prefrontal cortex, which subsequently causes the negative symptoms of schizophrenia, such as apathy and social withdraw. It has also been suggested, that increased dopaminergic activity in striatal areas is related to the wellknown positive schizophrenic symptoms, such as delusions and hallucinations. The present thesis addresses the regional effects of prototypical and atypical neuroleptics on nerve cell activity and dopaminergic tonus in three rat brain areas with special relevance for the pharmacological effects of neuroleptics. Finally, new pharmacological approaches to the medical treatment of schizophrenia are suggested based on our experimental results. Initially, the effects of the prototypical neuroleptic haloperidol and the atypical neuroleptic clozapine on nerve cell activity in the rat forebrain were investigated by measuring the regional expression of the FOS protein. The FOS protein is regarded as a marker of cellular activity and was measured by use of immunohistochemical techniques i) in the medial prefrontal cortex (PFC), probably involved in the negative symptoms of schizophrenia, ii) in the nucleus accumbens (NAc), probably involved in the positive symptoms of schizophrenia and iii) in the dorsolateral striatum (DLSt), most likely involved in the motoric side effects of neuroleptics. Clozapine increases FOS protein immunoreactivity in the PFC with no or minimal effects in the DLSt. In contrast, haloperidol increases FOS protein immunoreactivity in the DLSt with minor effect in the PFC. Other atypical neuroleptics (risperidone, sertindole and NNC 22-0031) induced a FOS protein expression pattern different from haloperidol: The atypical compounds exhibit a larger ratio between FOS protein expression in PFC and DLSt than measured for haloperidol. These results are in accordance with the reported beneficial effects of clozapine, risperidone and sertindole on negative symptoms of schizophrenia and their lower degree of motoric side effects compared to haloperidol. All neuroleptics induced FOS protein immunoreactivity in the NAc, in accordance with their ability to reduce positive psychotic symptoms in schizophrenics. The microdialysis technique was used to investigate the regional dopaminergic effects of the above mentioned antipsychotic compounds by measuring interstitial levels of the dopamine metabolite dihydroxyphenylacetic acid ([DOPAC]i) in PFC, NAc and DLSt. All antipsychotics tested increased [DOPAC]i in the NAc, whereas the atypical antipsychotics clozapine, risperidone, sertindole and NNC 22-0031--in contrast to haloperidol--preferentially increased [DOPAC]i in PFC compared to DLSt. Also these results are in concordance with the clinical effects of clozapine, risperidone, sertindole and haloperidol and support the hypothesis that reduced dopaminergic tone in the prefrontal cortex relates to the negative symptoms of schizophrenia. All clinically efficacious neuroleptics block central dopamine D2 receptors, which include the dopamine D2, D3 and D4 receptor subtypes. The present thesis characterizes a dopamine D3 receptor agonist, cis-OH-PBZI. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 3 | Dan Med Bull 2000 Jun 47: 151-67 |
| PMID | 10913983 |
| Title | Novel pharmacological approaches to the treatment of schizophrenia. |
| Abstract | schizophrenia is a devastating mental disease that affects the human population worldwide with an incidence of about 1%. Over the last decades basic and clinical research has considerably increased our understanding of the pathophysiology of schizophrenia, as well as the mechanism of action of antipsychotic compounds (neuroleptics), and new atypical neuroleptics with equipotent or improved antipsychotic effects and fewer motoric side effects have been developed. However, the pharmacological intervention does not effectively treat all the symptoms of the disease, and there is still a need for new, more effective antipsychotic compounds. Studies of brain function have demonstrated a reduced activation of prefrontal cortical areas during cognitive tasks in schizophrenics. It is hypothesized, that this hypofrontality is associated with a reduced dopaminergic tonus in the prefrontal cortex, which subsequently causes the negative symptoms of schizophrenia, such as apathy and social withdraw. It has also been suggested, that increased dopaminergic activity in striatal areas is related to the wellknown positive schizophrenic symptoms, such as delusions and hallucinations. The present thesis addresses the regional effects of prototypical and atypical neuroleptics on nerve cell activity and dopaminergic tonus in three rat brain areas with special relevance for the pharmacological effects of neuroleptics. Finally, new pharmacological approaches to the medical treatment of schizophrenia are suggested based on our experimental results. Initially, the effects of the prototypical neuroleptic haloperidol and the atypical neuroleptic clozapine on nerve cell activity in the rat forebrain were investigated by measuring the regional expression of the FOS protein. The FOS protein is regarded as a marker of cellular activity and was measured by use of immunohistochemical techniques i) in the medial prefrontal cortex (PFC), probably involved in the negative symptoms of schizophrenia, ii) in the nucleus accumbens (NAc), probably involved in the positive symptoms of schizophrenia and iii) in the dorsolateral striatum (DLSt), most likely involved in the motoric side effects of neuroleptics. Clozapine increases FOS protein immunoreactivity in the PFC with no or minimal effects in the DLSt. In contrast, haloperidol increases FOS protein immunoreactivity in the DLSt with minor effect in the PFC. Other atypical neuroleptics (risperidone, sertindole and NNC 22-0031) induced a FOS protein expression pattern different from haloperidol: The atypical compounds exhibit a larger ratio between FOS protein expression in PFC and DLSt than measured for haloperidol. These results are in accordance with the reported beneficial effects of clozapine, risperidone and sertindole on negative symptoms of schizophrenia and their lower degree of motoric side effects compared to haloperidol. All neuroleptics induced FOS protein immunoreactivity in the NAc, in accordance with their ability to reduce positive psychotic symptoms in schizophrenics. The microdialysis technique was used to investigate the regional dopaminergic effects of the above mentioned antipsychotic compounds by measuring interstitial levels of the dopamine metabolite dihydroxyphenylacetic acid ([DOPAC]i) in PFC, NAc and DLSt. All antipsychotics tested increased [DOPAC]i in the NAc, whereas the atypical antipsychotics clozapine, risperidone, sertindole and NNC 22-0031--in contrast to haloperidol--preferentially increased [DOPAC]i in PFC compared to DLSt. Also these results are in concordance with the clinical effects of clozapine, risperidone, sertindole and haloperidol and support the hypothesis that reduced dopaminergic tone in the prefrontal cortex relates to the negative symptoms of schizophrenia. All clinically efficacious neuroleptics block central dopamine D2 receptors, which include the dopamine D2, D3 and D4 receptor subtypes. The present thesis characterizes a dopamine D3 receptor agonist, cis-OH-PBZI. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 4 | Eur. J. Pharmacol. 2000 Dec 409: 57-65 |
| PMID | 11099700 |
| Title | Effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester on phencyclidine-induced effects in rats. |
| Abstract | Phencyclidine (PCP) is widely used as an animal model of schizophrenia. In rats, acute PCP treatment increased locomotor activity and induced stereotyped behaviours consisting of head weaving, turning and backpedalling. PCP had differential regional effects on c-FOS expression in rat brain, suggesting different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. To elucidate the role of nitric oxide, an important intracellular messenger, in the mechanism of action of PCP the effects of nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) were studied in PCP-treated animals. L-NAME potentiated PCP-induced behaviours and c-FOS expression in many brain regions. The greatest increases were observed in the frontal, retrosplenial granular cortex, cerebellum, thalamic and subthalamic nuclei. While PCP alone induced low c-FOS expression in the entorhinal cortex, with almost no expression in the rostral part of caudate putamen, animals pretreated with L-NAME showed marked activation in these brain areas. These results strongly indicate the involvement of the nitric oxide system in the mechanism of action of PCP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 5 | Neuropsychopharmacology 2000 Aug 23: 162-9 |
| PMID | 10882842 |
| Title | Clozapine- and olanzapine-induced Fos expression in the rat medial prefrontal cortex is mediated by beta-adrenoceptors. |
| Abstract | The atypical neuroleptics, clozapine and olanzapine, have superior therapeutic efficacy against the negative symptoms of schizophrenia, compared with the typical neuroleptics. Recently, it has been suggested that the ability of clozapine and olanzapine to induce FOS expression in the medial prefrontal cortex (mPFC), contribute to their therapeutic efficacy. However, the mechanisms underlying the neuropharmacological effects of clozapine and olanzapine in the mPFC remain elusive. In the present study, we demonstrate that clozapine- and olanzapine-induced FOS expression in the mPFC are inhibited by propranolol. We also show that clozapine and olanzapine induce FOS expression in the locus coeruleus. These results suggest that clozapine and olanzapine increase noradrenaline release by stimulating noradrenergic neuronal activity in the locus coeruleus and, consequently, increased noradrenaline induce FOS expression in the mPFC via beta-adrenergic receptors. This postulated sequence may be one of mechanisms by which clozapine-like atypical neuroleptics are more effective for the negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 6 | Ann. N. Y. Acad. Sci. 2000 Jun 911: 73-82 |
| PMID | 10911868 |
| Title | Molecular effects of the psychotropic NMDA receptor antagonist MK-801 in the rat entorhinal cortex: increases in AP-1 DNA binding activity and expression of Fos and Jun family members. |
| Abstract | Noncompetitive NMDA receptor antagonists such as phencyclidine and MK-801 produce psychotropic symptoms that closely resemble schizophrenic psychosis and induce the expression of immediate early genes in limbic cortical areas. We are concentrating on analyzing molecular and physiological effects that these drugs produce in the entorhinal cortex and on the potential connection between these effects and the psychotic symptoms. We show here that MK-801 increases the DNA binding activity of the activator protein-1 (AP-1) complex in the entorhinal cortex. We also observed increased expression of mRNAs for FOS and Jun transcription factor family members c-FOS, FOSB, Fra-2, and JunB, as well as FOS family proteins in the entorhinal cortex after MK-801 administration. This suggests that the activated AP-1 complex consists of these transcription factors. Genes regulated by the AP-1 complex in the entorhinal cortex might be involved in the pathophysiology of psychotic behavior and are potential targets for new antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 7 | Life Sci. 2000 Oct 67: 2865-72 |
| PMID | 11106001 |
| Title | The effect of the antipsychotic drug mosapramine on the expression of Fos protein in the rat brain: comparison with haloperidol, clozapine and risperidone. |
| Abstract | In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of FOS protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of FOS protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of FOS protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of FOS protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of FOS protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of FOS protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of FOS protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of FOS protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of FOS protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on FOS protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 8 | Br. J. Pharmacol. 2000 Jul 130: 1005-12 |
| PMID | 10882384 |
| Title | Blockade of phencyclidine-induced effects by a nitric oxide donor. |
| Abstract | 1. Phencyclidine (PCP) is widely used as an animal model of schizophrenia. The aim of this study was to better understand the role of nitric oxide (NO) in the mechanism of action of PCP and to determine whether positive NO modulators may provide a new approach to the treatment of schizophrenia. 2. The effects of the NO donor, sodium nitroprusside (SNP), were studied in PCP-treated rats. Following drug administration, behavioural changes and the expression of c-FOS, a metabolic marker of functional pathways in the brain, were simultaneously monitored. 3. Acute PCP (5 mg kg(-1), i. p.) treatment induced a complex behavioural syndrome, consisting of hyperlocomotion, stereotyped behaviours and ataxia. Treatment with SNP (2 - 6 mg kg(-1), i.p.) by itself produced no effect on any behaviour studied but completely abolished PCP-induced behaviour in a dose- and time-dependent manner. 4. PCP had differential regional effects on c-FOS expression in rat brain, suggesting regionally different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. Pre-treatment with SNP blocked PCP-induced c-FOS expression at doses similar to those that suppress PCP-induced behavioural effects. 5. These results implicate the NO system in the mechanism of action of PCP. The fact that SNP abolished effects of PCP suggests that drugs targeting the glutamate-NO system may represent a novel approach to the treatment of PCP-induced psychosis and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 9 | Brain Res. 2000 Apr 863: 112-9 |
| PMID | 10773199 |
| Title | Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine. |
| Abstract | Disturbances of retinoid activated transcription mechanisms have recently been implicated as risk factors for schizophrenia. In this study we have compared the regulation of mRNAs for the nuclear orphan receptor NGFI-B, which forms a functional heterodimer with the retinoid x receptor and the related orphan nuclear receptor Nor1 with c-FOS mRNA after acute and chronic treatments with haloperidol and clozapine. The antipsychotic drugs haloperidol and clozapine have different clinical profiles. Haloperidol is a typical neuroleptic giving extrapyramidal side effects (EPS), whereas the atypical compound clozapine does not. Acute haloperidol treatment increased NGFI-B, Nor1 and c-FOS mRNAs in nucleus accumbens shell and core as well as medial and lateral caudate putamen. In contrast, clozapine lead to an increase of NGFI-B, Nor1 and c-FOS only in the accumbens shell. No haloperidol or clozapine effect on these mRNAs was detected in cingulate, sensory or motor cortex. Chronic haloperidol lead to an increase of NGFI-B mRNA in the accumbens core. Acutely, it is possible that the increased levels of NGFI-B, Nor1 and c-FOS mRNA levels in striatum and accumbens might indicate a neural activation which possibly can be used when screening for drugs that do not produce EPS. Also, the increased levels of NGFI-B, which is an important component in retinoid signaling, both after acute and chronic treatments of haloperidol suggests altered sensitivity to retinoids which could be an important component for the beneficial antipsychotic effect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 10 | Eur. J. Pharmacol. 2000 Jun 398: 1-10 |
| PMID | 10856442 |
| Title | Effects of antipsychotic drugs on neurotoxicity, expression of fos-like protein and c-fos mRNA in the retrosplenial cortex after administration of dizocilpine. |
| Abstract | In this study, we examined the effect of clozapine, olanzapine, risperidone and haloperidol on the neuropathology (i.e. neuronal vacuolization) and the expression of FOS-like protein and c-FOS mRNA in the retrosplenial cortex of female Sprague-Dawley rats induced by the NMDA receptor antagonist dizocilpine. Pretreatment (15 min) with clozapine or olanzapine, but not risperidone or haloperidol, blocked the neuronal vacuolization produced by dizocilpine (0.5 mg/kg, s.c.) in the rat retrosplenial cortex in a dose-dependent manner. Furthermore, pretreatment (15 min) with clozapine or olanzapine, but not risperidone or haloperidol, significantly attenuated the expression of FOS-like protein in the retrosplenial cortex induced by dizocilpine (0.5 mg/kg, s.c.) in a dose-dependent manner. The marked expression of c-FOS mRNA in the rat retrosplenial cortex induced by the administration of dizocilpine (0.5 mg/kg, s.c.) was significantly attenuated by pretreatment (15 min) with clozapine (10 mg/kg) or olanzapine (10 mg/kg), but not risperidone (10 mg/kg) or haloperidol (10 mg/kg). The present results suggest that pharmacologically relevant doses of clozapine or olanzapine, but not risperidone or haloperidol, block the neuropathological changes and the expression of FOS-like protein and c-FOS mRNA in the rat retrosplenial cortex elicited by the administration of dizocilpine. It is possible that the blockade of dizocilpine-induced neuropathological changes by clozapine and olanzapine may be related to the unique antipsychotic actions of these drugs in schizophrenic patients, although this remains to be verified. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 11 | J Psychiatry Neurosci 2001 Nov 26: 385-94 |
| PMID | 11762206 |
| Title | How do the atypical antipsychotics work? |
| Abstract | Understanding the action of atypical antipsychotics is useful in exploring the pathophysiology of schizophrenia and in synthesizing drugs that improve various domains of psychopathology without unwanted side effects. In animal models, atypical antipsychotic drugs appear to have a preferential action in the limbic dopaminergic system. Regionally specific action has been studied by measuring the amount of FOS protein produced in a particular brain region as a consequence of a drug's effects on the c-FOS gene. Evidence suggests that the atypical and typical antipsychotic drug-induced increases in FOS levels in the nucleus accumbens are related to improvements in positive symptoms, whereas FOS increases in the prefrontal cortex, with the atypical antipsychotics only, correlate with negative symptom improvement. The extrapyramidal effects seen with typical antipsychotics are thought to be related to FOS increases in the striatonigral pathway. However, studies of FOS levels in specific brain regions reveal only the site of action, not the mode of action. The finding that atypicality is related to surmountable D2 dopamine receptor blocking provides another venue to define and explore atypical antipsychotic drug action. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 12 | Biol. Psychiatry 2001 Oct 50: 510-20 |
| PMID | 11600104 |
| Title | Olanzapine activates the rat locus coeruleus: in vivo electrophysiology and c-Fos immunoreactivity. |
| Abstract | Activation of central noradrenergic pathways by atypical antipsychotics has been hypothesized to play a role in their efficacy in treating the negative symptoms and cognitive impairment of schizophrenia. Because acute administration of the atypical antipsychotic olanzapine has been shown to increase extracellular levels of norepinephrine in the medial prefrontal cortex, we examined the effects of olanzapine on the noradrenergic cells of the locus coeruleus (LC). The effects of olanzapine (0.25-16 mg kg(-1), IV) on the firing rates and patterns of LC neurons were determined by extracellular, single-unit recordings in chloral hydrate-anaesthetized rats. The effects of olanzapine and clozapine on c-FOS expression in the LC, nucleus subcoeruleus part alpha (SubCA), and nucleus A5 (A5) were studied by immunohistochemistry. Olanzapine increased LC cell firing rates, de-regularized firing, and induced burst firing. Induction of c-FOS expression in the LC by olanzapine and clozapine was confirmed and was also found in the SubCA, but not in A5. Acute administration of olanzapine activates the noradrenergic neurons of the rat LC. This increased activity of LC neurons may play an important role in the efficacy of olanzapine and clozapine in treating both the negative symptoms and cognitive impairment observed in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 13 | Biol. Psychiatry 2001 Oct 50: 510-20 |
| PMID | 11600104 |
| Title | Olanzapine activates the rat locus coeruleus: in vivo electrophysiology and c-Fos immunoreactivity. |
| Abstract | Activation of central noradrenergic pathways by atypical antipsychotics has been hypothesized to play a role in their efficacy in treating the negative symptoms and cognitive impairment of schizophrenia. Because acute administration of the atypical antipsychotic olanzapine has been shown to increase extracellular levels of norepinephrine in the medial prefrontal cortex, we examined the effects of olanzapine on the noradrenergic cells of the locus coeruleus (LC). The effects of olanzapine (0.25-16 mg kg(-1), IV) on the firing rates and patterns of LC neurons were determined by extracellular, single-unit recordings in chloral hydrate-anaesthetized rats. The effects of olanzapine and clozapine on c-FOS expression in the LC, nucleus subcoeruleus part alpha (SubCA), and nucleus A5 (A5) were studied by immunohistochemistry. Olanzapine increased LC cell firing rates, de-regularized firing, and induced burst firing. Induction of c-FOS expression in the LC by olanzapine and clozapine was confirmed and was also found in the SubCA, but not in A5. Acute administration of olanzapine activates the noradrenergic neurons of the rat LC. This increased activity of LC neurons may play an important role in the efficacy of olanzapine and clozapine in treating both the negative symptoms and cognitive impairment observed in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 14 | Behav. Brain Res. 2001 Sep 124: 71-6 |
| PMID | 11423167 |
| Title | Enhancement of immobility induced by repeated phencyclidine injection: association with c-Fos protein in the mouse brain. |
| Abstract | Immunohistochemistry of c-FOS protein was performed to study changes in neuronal activity in discrete brain areas of mice repeatedly treated with phencyclidine (PCP) showing enhancement of immobility in the forced swimming test, this behavioral change being considered as avolition, which is one of negative symptoms of schizophrenia. Repeated treatment with PCP significantly prolonged immobility time in the forced swimming test, compared with saline treatment. The c-FOS protein expression of mice showing PCP-induced enhancement of immobility was increased in certain brain regions, such as the retrosplenial cortex, pyriform cortices, pontine nuclei, cingulate, frontal cortex and thalamus, compared with that of PCP-treated, non-swimming and saline-treated, swimming groups. These results suggest that increased c-FOS protein is involved in the expression of PCP-induced enhancement of immobility, and c-FOS expression plays a role in negative symptoms-like behavioral changes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 15 | Brain Res. 2001 Jan 888: 302-305 |
| PMID | 11150488 |
| Title | The effects of phencyclidine pretreatment on amphetamine-induced behavior and c-Fos expression in the rat. |
| Abstract | Previous data demonstrate that a single injection of phencyclidine enhances amphetamine-induced behaviors 24 h later, suggesting that the delayed effects of a single dose of phencyclidine may produce a schizophrenia-like state in animals. These behavioral changes were accompanied by altered patterns of c-FOS induction, suggesting possible neurochemical correlates to the observed behaviors. Because investigations into PCP's ability to model schizophrenia have found that the effects of repeated, or subchronic, PCP administration differ according to the dose and administration paradigm, this study sought to determine whether single and subchronic PCP exposure produce different effects on amphetamine-induced behaviors and c-FOS induction. No differences were observed between these administration paradigms; both single and subchronic PCP exposure enhanced amphetamine-induced c-FOS in the striatum, decreased c-FOS in the prefrontal cortex, and decreased the number of cage-crossings. However, the observation that PCP pretreatment affected c-FOS induction in the same manner observed previously while having an opposite effect on amphetamine-induced behavior suggests that these behavioral and neurochemical effects are dissociated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 16 | Brain Res. Bull. 2001 Jan 54: 145-51 |
| PMID | 11275403 |
| Title | Neural correlates of sensory gating in the rat: decreased Fos induction in the lateral septum. |
| Abstract | In the P(50) gating or conditioning-testing paradigm in the rat, two identical click stimuli are presented with an inter-click interval of 500 ms. The reaction towards the second click, as measured with evoked potentials, is reduced in respect to that towards the first click; this phenomenon is called sensory gating. In the present experiments, the inter-click interval was varied systematically and auditory evoked potentials were measured. Sensory gating was found to occur only at intervals between 500 and 1000 ms, but not at longer intervals. FOS immunohistochemistry was then performed using two groups of rats exposed to double clicks: the inter-click interval was 500 ms in the experimental group and 2500 ms in the control group. FOS induction was analyzed in selected brain structures. In the auditory pathways, FOS-immunoreactive neurons were found in both groups of rats in the inferior colliculus and medial geniculate body. FOS-immunoreactive cells were also examined in the septum and hippocampus. In the ventral part of the lateral septal nucleus, the labeled neurons were significantly fewer in the experimental animals compared to the control group. Smaller and non-significant quantitative differences of FOS-positive neurons were documented in the medial septum and hippocampal CA1 region. These data point out a selective decrease in the lateral septum of FOS induced by auditory sensory gating, and suggest an involvement of this structure, and possibly of other parts of the septo-hippocampal system, in sensory gating mechanisms. The results might be relevant for theories on sensory gating deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 17 | Psychopharmacology (Berl.) 2001 May 155: 299-309 |
| PMID | 11432693 |
| Title | Lack of phencyclidine-induced effects in mice with reduced neuronal nitric oxide synthase. |
| Abstract | Phencyclidine (PCP) is widely used as an animal model of schizophrenia, because in humans it can induce positive and negative symptoms associated with schizophrenia. PCP is an antagonist of N-methyl-D-aspartate receptors, which are associated with the nitric oxide (NO) system. The primary objective was to determine whether neuronal NO synthase (nNOS) is involved in PCP-induced behaviours and neuronal activation, as measured by the expression of c-FOS. After characterizing a PCP mouse model (dose-response study, Experiment 1), we measured PCP-induced effects in mice treated with nNOS antisense oligodeoxynucleotides (AS-ODNs) (Experiment 2), and in nNOS knockout (nNOS-/-) mice (Experiment 3). PCP 5 mg/kg induced the maximum behavioural effects of all doses tested, consisting of hyperlocomotion, stereotyped turning behaviour, without the presence of ataxia. PCP also induced an increase in FOS-like immunoreactivity (FOS-LIR) in the frontal cortex, as well as in the midline limbic (thalamic and hypothalamic nuclei) areas. In the AS-ODN-treated mice, PCP induced less behaviour when compared to water-treated controls. In the nNOS-/- mice, PCP induced less behaviour and a decrease in FOS-LIR in the frontal cortex and midline limbic areas, when compared to wild-type littermate controls. Our findings suggest that the frontal cortex and midline thalamic brain regions are involved in PCP-induced effects in mice. Furthermore, we show that an intact nNOS system is necessary to obtain PCP-induced effects. This may implicate nNOS as a viable drug target in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 18 | Synapse 2001 Apr 40: 11-8 |
| PMID | 11170217 |
| Title | Neonatal phencyclidine treatment selectively attenuates mesolimbic dopamine function in adult rats as revealed by methamphetamine-induced behavior and c-fos mRNA expression in the brain. |
| Abstract | One of the major hypotheses regarding the pathogenesis of schizophrenia is the implication of neurodevelopmental abnormality. However, the mechanism of delayed onset of schizophrenic symptoms, in which increased dopaminergic activity in mesolimbic or mesocortical dopamine systems plays a pathological role, is not known. In this study, we investigated whether the chronic blockade of N-methyl-D-aspartate (NMDA) receptor by phencyclidine (PCP), an NMDA channel blocker, during development could disrupt the dopamine system during later life. Neonatal rats were injected with PCP subcutaneously daily from postnatal day (PD) 1 to PD 14 and their dopaminergic function was evaluated on PD 42 by rating the methamphetamine (MAP)-induced behavior. To illustrate the activated brain regions, the expression of c-FOS mRNA in response to a MAP challenge was also studied utilizing in situ hybridization. Chronic neonatal PCP treatment attenuated MAP-induced oral stereotypy (licking and gnawing) and reduced MAP-induced expression of c-FOS mRNA in the N. accumbens shell region and VTA but not in the N. accumbens core region, medial striatum, or substantia nigra. These results suggest that neonatal blockade of NMDA receptor, which induces a number of effects in the developing nervous system, may cause long-lasting functional changes of the mesolimbic dopamine system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 19 | Synapse 2001 Apr 40: 11-8 |
| PMID | 11170217 |
| Title | Neonatal phencyclidine treatment selectively attenuates mesolimbic dopamine function in adult rats as revealed by methamphetamine-induced behavior and c-fos mRNA expression in the brain. |
| Abstract | One of the major hypotheses regarding the pathogenesis of schizophrenia is the implication of neurodevelopmental abnormality. However, the mechanism of delayed onset of schizophrenic symptoms, in which increased dopaminergic activity in mesolimbic or mesocortical dopamine systems plays a pathological role, is not known. In this study, we investigated whether the chronic blockade of N-methyl-D-aspartate (NMDA) receptor by phencyclidine (PCP), an NMDA channel blocker, during development could disrupt the dopamine system during later life. Neonatal rats were injected with PCP subcutaneously daily from postnatal day (PD) 1 to PD 14 and their dopaminergic function was evaluated on PD 42 by rating the methamphetamine (MAP)-induced behavior. To illustrate the activated brain regions, the expression of c-FOS mRNA in response to a MAP challenge was also studied utilizing in situ hybridization. Chronic neonatal PCP treatment attenuated MAP-induced oral stereotypy (licking and gnawing) and reduced MAP-induced expression of c-FOS mRNA in the N. accumbens shell region and VTA but not in the N. accumbens core region, medial striatum, or substantia nigra. These results suggest that neonatal blockade of NMDA receptor, which induces a number of effects in the developing nervous system, may cause long-lasting functional changes of the mesolimbic dopamine system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 20 | Neuroscience 2001 -1 104: 717-30 |
| PMID | 11440804 |
| Title | Interactions between environmental stimulation and antipsychotic drug effects on forebrain c-fos activation. |
| Abstract | The immediate-early gene product FOS is differentially induced in the rat brain by the antipsychotic drugs haloperidol and clozapine. It is often claimed that although both drugs induce FOS in the nucleus accumbens, haloperidol but not clozapine increases FOS-like immunoreactivity in the striatum, whereas clozapine but not haloperidol increases FOS-like immunoreactivity in prefrontal cortex. Investigations of antipsychotic drug effects on FOS have typically administered high doses with pronounced sedative effects to behaviorally naive animals. In the present study, we compared the effects of low doses of haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) on FOS-like immunoreactivity in rats which were either behaviorally naive, exposed to a novel environment or tested for two-way active avoidance. We determined that haloperidol increased FOS in the striatum and nucleus accumbens regardless of testing condition whereas clozapine markedly reduced the induction of FOS by behavioral testing in these regions; moreover, haloperidol dramatically increased prefrontal cortical FOS expression in animals placed in a novel environment, but not in testing-naive controls. From these results we suggest that antipsychotic drug-induced patterns of FOS expression in the rat are highly dependent on animals' concurrent behavioral status, perhaps reflecting neuroanatomically specific interactions between antipsychotic drugs and environmental stressors which also may occur in the schizophrenic condition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 21 | Curr Drug Targets CNS Neurol Disord 2002 Apr 1: 163-81 |
| PMID | 12769625 |
| Title | Muscarinic receptors as a target for drugs treating schizophrenia. |
| Abstract | The family of 5 muscarinic acetylcholine receptors belongs to the superfamily of G protein coupled neurotransmitter receptors that serve in part as regulators of synaptic function. Muscarinic receptors are anatomically positioned in cortical and subcortical areas and modulate dopaminergic and glutamatergic neurotransmission thought to be dysfunctional in schizophrenia. Neurochemical studies have shown that dopamine and muscarinic receptors reciprocally modulate one another. For example, the muscarinic agonist xanomeline increases extracellular levels of dopamine and FOS expression in cortical areas greater than subcortical areas, similar to effects of atypical antipsychotics. In electrophysiological studies, xanomeline with acute and chronic administration decreased firing of the mesocorticolimbic dopamine A10 tract, but not the motoric dopamine A9 tract. Behavioral investigations have shown that muscarinic agonists, like dopamine antagonists, inhibit conditioned-avoidance responding and dopamine-agonist-induced behaviors including hyperactivity, climbing behavior and disruption of prepulse inhibition, models for positive symptoms of schizophrenia. Transgenic knockout mice lacking M(4) receptors are hyperactive and hyper-responsive to dopamine D(1) agonists, suggesting a dynamic balance between the dopamine and M(4) receptors. Muscarinic agonists had activity in animal models of negative symptoms, cognitive dysfunction and affective disorders, symptoms that are prominent in schizophrenic patients. Consistent with effects in animal models, preliminary clinical investigation indicates that muscarinic agonists like xanomeline may be effective in the pharmacotherapy of schizophrenia. Thus, we hypothesize that a combined M(1) agonist to promote cognition and a M(4) agonist for antipsychotic-like effects would treat the symptom domains of schizophrenia without parasympathomimetic side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 22 | Ann. N. Y. Acad. Sci. 2002 Jun 965: 180-92 |
| PMID | 12105094 |
| Title | Neurochemical changes and neurotoxic effects of an acute treatment with sydnocarb, a novel psychostimulant: comparison with D-amphetamine. |
| Abstract | Sydnocarb [(phenylisopropyl)N-phenylcarbamoylsydnonimine; SYD] was introduced to clinical practice in Russia as a psychostimulant drug used for the treatment of asthenia and apathy, which accompany schizophrenia and manic depression. It has been described as a psychostimulant with addiction liability and toxicity less than amphetamine (AMPH). The precise cellular mechanisms by which sydnocarb elicits its psychostimulant effect are still unclear. At present its neurochemical and neurotoxic effects are compared to those of AMPH in the striatum, the main input structure of the basal ganglia. The expression of c-FOS protein in striatal neurons was much more increased after a single injection of D-AMPH (5 mg/kg) than after an equimolar concentration of SYD (23.8 mg/kg) in both the anterior and the posterior part of the striatum. Using in situ hybridization on striatal slices, we observed that AMPH increased the striatal levels of preprodynorphin (PPDYN) mRNAs in both parts of the striatum, while SYD did not affect basal levels of PPDYN mRNAs. Furthermore, AMPH and SYD increased striatal preprotachykinin (PPT-A) and preproenkephalin (PPE) mRNA levels. The effects of AMPH and SYD on PPT-A-mRNA levels were similar. A differential effect of AMPH and SYD was observed only on the PPE-mRNA levels measured in the anterior striatum where SYD increased these levels more than AMPH. The acute neurotoxicity of these two psychostimulants was analyzed by measuring their effects on the parameters of oxidative stress, such as nitric oxide (NO) generation, as well as specific indices of lipid peroxidation (i.e., thiobarbituric acid reactive substances; TBARS), while, on the other hand, the alpha-tocopherol level was taken as an index of antioxidant defense processes. Measuring generation of NO directly by electron paramagnetic resonance, it was observed that AMPH shows a more pronounced increase in comparison to SYD, in the striatum and in cortex. TBARS levels in the striatum and cortex were significantly less enhanced than AMPH after a single injection of SYD. Similarly, the alpha-tocopherol level was decreased only by AMPH in the striatum, and neither AMPH nor SYD had any effect in the cortex. Results show that a single injection of a high dose of AMPH is able to induce several neurotoxic effects. The study also demonstrates that SYD has mild neurochemical effects as well as fewer neurotoxic properties than AMPH. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 23 | Neuroscience 2002 -1 112: 697-705 |
| PMID | 12074911 |
| Title | Isolation rearing in the rat disrupts the hippocampal response to stress. |
| Abstract | Both human schizophrenia and the effects of isolation rearing in rats produce deficits in hippocampal and cortical functioning. This study was concerned with identifying changes associated with altered neuronal function in the rat hippocampus following isolation rearing. Rats were isolated from weaning at 21 days postnatal for 6 weeks and the hippocampal sensitivity to isolation rearing and stress were studied using c-FOS immunohistochemistry and in vivo microdialysis. Isolation rearing altered neuronal activity measured by FOS-like immunoreactivity in the specific brain areas as measured by either increased or reduced expression. Basal neuronal activity in the ventral CA1 hippocampus in isolation-reared rats was notably higher compared to group-reared rats but markedly lower FOS-like immunoreactivity was found in the central and basolateral nuclei of the amygdala. Exposure to stress produced differential effects on neuronal activity in isolation-reared rats between the dorsal and ventral hippocampus, with increased FOS-like immunoreactivity in the dorsal hippocampus but lower FOS-like immunoreactivity in the ventral hippocampus compared to group-reared rats. These results indicate that isolation rearing may alter the relationship between hippocampal neuronal function in the dorsal and ventral hippocampus. An in vivo microdialysis study showed that systemically administered parachloroamphetamine (2.5 mg/kg, i.p.) enhanced extracellular 5-hydroxytryptamine (5-HT) in the dorsal hippocampus in group-reared but not in isolation-reared rats. Restraint stress had no effect on hippocampal extracellular 5-HT in group-reared rats but reduced levels in isolation-reared rats during the period of restraint. Inescapable mild footshock produced a marked increase in extracellular hippocampal 5-HT in group-reared but not isolation-reared rats. Overall the results provide extensive evidence that isolation rearing alters presynaptic 5-HT hippocampal function and that the neuronal response to stress is altered by isolation. Isolation rearing in the rat alters hippocampal function, including the serotonergic system, leading to changes in neurotransmitter systems in other brain areas. These changes may model aspects of human neurodevelopmental disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 24 | Curr Drug Targets CNS Neurol Disord 2002 Apr 1: 163-81 |
| PMID | 12769625 |
| Title | Muscarinic receptors as a target for drugs treating schizophrenia. |
| Abstract | The family of 5 muscarinic acetylcholine receptors belongs to the superfamily of G protein coupled neurotransmitter receptors that serve in part as regulators of synaptic function. Muscarinic receptors are anatomically positioned in cortical and subcortical areas and modulate dopaminergic and glutamatergic neurotransmission thought to be dysfunctional in schizophrenia. Neurochemical studies have shown that dopamine and muscarinic receptors reciprocally modulate one another. For example, the muscarinic agonist xanomeline increases extracellular levels of dopamine and FOS expression in cortical areas greater than subcortical areas, similar to effects of atypical antipsychotics. In electrophysiological studies, xanomeline with acute and chronic administration decreased firing of the mesocorticolimbic dopamine A10 tract, but not the motoric dopamine A9 tract. Behavioral investigations have shown that muscarinic agonists, like dopamine antagonists, inhibit conditioned-avoidance responding and dopamine-agonist-induced behaviors including hyperactivity, climbing behavior and disruption of prepulse inhibition, models for positive symptoms of schizophrenia. Transgenic knockout mice lacking M(4) receptors are hyperactive and hyper-responsive to dopamine D(1) agonists, suggesting a dynamic balance between the dopamine and M(4) receptors. Muscarinic agonists had activity in animal models of negative symptoms, cognitive dysfunction and affective disorders, symptoms that are prominent in schizophrenic patients. Consistent with effects in animal models, preliminary clinical investigation indicates that muscarinic agonists like xanomeline may be effective in the pharmacotherapy of schizophrenia. Thus, we hypothesize that a combined M(1) agonist to promote cognition and a M(4) agonist for antipsychotic-like effects would treat the symptom domains of schizophrenia without parasympathomimetic side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 25 | Neuropsychopharmacology 2002 Dec 27: 906-13 |
| PMID | 12464447 |
| Title | Homer 1a gene expression modulation by antipsychotic drugs: involvement of the glutamate metabotropic system and effects of D-cycloserine. |
| Abstract | N-methyl-D-aspartate receptor hypofunction has been suggested to play a role in the pathophysiology of schizophrenia. New glutamatergic mechanisms involving metabotropic receptors have been recently proposed to further expand this hypothesis. "Homer" is a family of postsynaptic density proteins functionally and physically attached to glutamate metabotropic receptors. We investigated the activation of the early gene form of Homer after acute treatment with typical or atypical antipsychotic drugs alone or with the adjunction of D-cycloserine. This activation was compared with that of c-FOS, considered a putative molecular marker of brain regions activated by antipsychotics. Male Sprague-Dawley rats were treated intraperitoneally with haloperidol (0.8 mg/Kg) or clozapine (15 mg/Kg) alone or with the adjunction of D-cycloserine (20 mg/Kg). Rats were sacrificed ninety minutes after injection and the brains were processed for quantitative in situ hybridization histochemistry. Haloperidol induced a statistically significant increase of Homer both in caudate-putamen and nucleus accumbens compared with controls; clozapine induced Homer significantly only in the accumbens. The adjunction of D-cycloserine attenuated the haloperidol-induced increase of Homer expression in caudate-putamen and nucleus accumbens and attenuated the clozapine-induced increase in the accumbens. The c-FOS gene expression was potently induced by haloperidol in caudate-putamen and nucleus accumbens, and by clozapine only in the accumbens. The adjunction of D-cycloserine enhanced c-FOS expression only for clozapine in both regions of the forebrain. These results demonstrate a differential involvement of glutamatergic metabotropic system in gene expression modulation induced by typical or atypical antipsychotic drugs and may suggest new molecular basis for the augmentation strategy by a glycine site partial agonist. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 26 | Neuropharmacology 2002 Sep 43: 394-407 |
| PMID | 12243769 |
| Title | Induction of differential patterns of local cerebral glucose metabolism and immediate-early genes by acute clozapine and haloperidol. |
| Abstract | Atypical antipsychotic drugs, such as clozapine, show many differences in their actions as compared to typical antipsychotic drugs, such as haloperidol. In particular, the neuroanatomical substrates responsible for the superior therapeutic profile of clozapine are unknown. In order to identify regions of the CNS which are affected either differentially or in parallel by clozapine and haloperidol, we have used 2-deoxyglucose autoradiography to monitor local cerebral glucose utilisation (LCGU), in parallel with in situ hybridisation to monitor the expression of five immediate-early genes (c-FOS, FOS B, fra 1, fra 2 and zif 268). Clozapine (20 mg/kg i.p.) caused a reduction in LCGU in many areas of the psychosis-related corticolimbothalamic and Papez circuits, such as the anterior cingulate and retrosplenial cortices and the mammillary body. Haloperidol (1 mg/kg i.p.) showed less ability to modulate LCGU in these regions. Clozapine also increased immediate-early gene expression in these limbic circuits, although the pattern of induction was different for each gene, and also differed from the pattern of effects on LCGU. The only region which displayed similar effects with both antipsychotics was the anteroventral thalamus, with LCGU and c-FOS mRNA expression being altered similarly by both drugs. This further supports the hypothesis of the thalamus being a common site of antipsychotic action. Since the Papez circuit has been implicated in emotive learning, and to be involved in mediating the negative symptoms associated with schizophrenia, the greater action of clozapine on regions within this circuit may also provide clues to the atypical antipsychotic's superior efficacy against negative symptoms. This is one of the first studies which provides a direct comparison of regional activity as assessed by LCGU and by a panel of IEGs. The results emphasise the necessity of monitoring a number of different parameters of regional activity in order to identity the neuroanatomical substrate for actions of a drug in the CNS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 27 | Eur Neuropsychopharmacol 2002 Oct 12: 379-86 |
| PMID | 12208555 |
| Title | Biochemical effects in brain of low doses of haloperidol are qualitatively similar to those of high doses. |
| Abstract | Typical and atypical antipsychotic drugs (APD) show differential effects in brain on both dopamine output and activation of FOS-like immunoreactivity (FLI) in dopamine nerve terminal regions. Typical APD increase dopamine output preferentially in the core and atypical APD increase dopamine output preferentially in the shell of the nucleus accumbens (NAC). Whereas both typical and atypical APD increase FLI in NAC, typicals cause FLI activation in the striatum and atypicals cause FLI activation in the prefrontal cortex. Clinically, low doses of haloperidol cause less side-effects than higher doses, and low-dose haloperidol has been suggested as a cost-effective alternative to atypical APD. Here, in vivo voltammetry in anaesthetised, pargyline-pretreated rats was used to measure dopamine output in the two subdivisions of the NAC and, in addition, immunohistochemistry was used to assess FLI activation in dopamine target areas, following acute haloperidol administration. Haloperidol, 0.001 and 0.01 mg/kg i.v., caused a significantly higher dopamine output in the core than in the shell of the NAC. Moreover, haloperidol 0.05 and 0.5, but not 0.005, mg/kg s.c. increased FLI in the NAC and the striatum, but not in the medial prefrontal cortex. Thus, even extremely low doses of haloperidol generate, in principle, the same biochemical effects in brain as higher doses, and these effects remain different from those of atypical APD. These biological data indicate that clinical differences between haloperidol and atypicals are qualitative rather than dose-dependent. Consequently, our results do not support the use of low-dose haloperidol as replacement for atypical APD in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 28 | J. Neurosci. 2002 Aug 22: 7272-80 |
| PMID | 12177222 |
| Title | Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat. |
| Abstract | By using double in situ hybridization performed with proenkephalin and H3-receptor riboprobes on the same sections from rat brain, we show that histamine H3 receptors are expressed within striatopallidal neurons of the indirect movement pathway. The majority ( approximately 70%) of striatal enkephalin neurons express H3-receptor mRNAs. This important degree of coexpression of proenkephalin and H3-receptor mRNAs prompted us to explore the effect of H3-receptor ligands on the regulation of enkephalin mRNA expression in the striatum. Acute administration of ciproxifan, a H3-receptor antagonist/inverse agonist, did not modify the expression of the neuropeptide by itself but strongly increased the upregulation of its expression induced by haloperidol. This potentiation (1) was suppressed by the administration of (R)-alpha-methylhistamine, a H3-receptor agonist, (2) occurred both in the caudate-putamen and nucleus accumbens, and (3) was also observed with a similar pattern on c-FOS and neurotensin mRNA expression. Similarly, whereas it was devoid of any motor effect when used alone, ciproxifan strongly potentiated haloperidol-induced locomotor hypoactivity and catalepsy, two behaviors in which striatal neurons are involved. The strong H3-receptor mRNA expression in enkephalin neurons suggests that the synergistic neurochemical and motor effects of ciproxifan and haloperidol result from direct H3/D2-receptor interactions, leading to an enhanced activation of striatopallidal neurons of the indirect movement pathway. The potentiation of the effects of haloperidol by ciproxifan strengthens the potential interest of H3-receptor antagonists/inverse agonists to improve the symptomatic treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 29 | Curr Opin Investig Drugs 2002 Jan 3: 113-20 |
| PMID | 12054061 |
| Title | Aripiprazole (Otsuka Pharmaceutical Co). |
| Abstract | Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-FOS mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484]. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 30 | Eur. J. Neurosci. 2002 Feb 15: 713-20 |
| PMID | 11886451 |
| Title | Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum. |
| Abstract | Administration of typical antipsychotic drugs (APDs) is often accompanied by extrapyramidal side-effects (EPS). Treatment with atypical APDs has a lower incidence of motor side-effects and atypical APDs are superior to typical APDs in treating the negative symptoms of schizophrenia. Although typical APDs strongly induce the immediate-early gene c-FOS in the striatum while atypical APDs do so only weakly, it is possible that the effects of atypical APDs are more pronounced within certain regions of the striatum. The striatum contains two histochemically defined compartments, the striosome (patch) and the matrix. These compartments have been well characterized anatomically but their functional attributes are unclear. We therefore examined the effects of typical and atypical APDs on FOS expression in the striosome and matrix of the rat. Typical and atypical APDs were distinguished by the pattern of striatal compartmental activation they induced: the striosome : matrix ratio of FOS-li neurons was greater in rats treated with atypical APDs. Pretreating animals with selective antagonists of receptors that atypical APDs target with high affinity did not increase the striosome : matrix FOS ratio of typical APD-treated rats and thus did not mimic the ratio seen in response to atypical APDs. However, pretreatment with the atypical APD clozapine did recapitulate the characteristic compartmental FOS pattern seen in response to typical APDs. These data suggest that some characteristics of atypical APDs, such as the lower EPS liability and greater reduction of negative symptoms, may be linked to the coordinate regulation of the striatal striosome and matrix. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 31 | Science 2003 Nov 302: 1412-5 |
| PMID | 14631045 |
| Title | Diverse psychotomimetics act through a common signaling pathway. |
| Abstract | Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (cAMP)-regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase-1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase-3 (GSK-3), cAMP response element-binding protein (CREB), and c-FOS. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters-sensorimotor gating and repetitive movements-were strongly attenuated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 32 | Neuropsychopharmacology 2003 Aug 28: 1506-14 |
| PMID | 12799614 |
| Title | Increased expression of c-Jun transcription factor in cerebellar vermis of patients with schizophrenia. |
| Abstract | In the cerebellar vermis of schizophrenic patients, our previous studies have revealed alterations in the mitogen-activated protein (MAP) kinase signaling cascade and downstream transcription factors within the c-FOS promoter. Since the proteins of the FOS and Jun families of immediate-early genes dimerize to form activating protein (AP)-1, the present study was conducted to examine the expression of Jun transcription factors in schizophrenic and control subjects. Using Western blot analysis, we determined the protein levels of c-Jun, Jun B, and Jun D as well as the levels of c-jun mRNA by relative RT-PCR in post-mortem samples from cerebellar vermis. The expression of c-Jun protein and c-jun mRNA was significantly increased in the cerebellar vermis of patients with schizophrenia, whereas no significant differences were found in the expression of Jun B or Jun D proteins. Studies in rats indicated that the abnormal expression of c-Jun transcription factor observed in schizophrenic patients was not related to post-mortem intervals or chronic treatment with antipsychotic medications. This study provides new insights into cerebellar abnormalities of schizophrenia at the level of expression of c-Jun that target key genes associated with the MAP kinase cascade. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 33 | Neuropsychopharmacology 2003 Aug 28: 1506-14 |
| PMID | 12799614 |
| Title | Increased expression of c-Jun transcription factor in cerebellar vermis of patients with schizophrenia. |
| Abstract | In the cerebellar vermis of schizophrenic patients, our previous studies have revealed alterations in the mitogen-activated protein (MAP) kinase signaling cascade and downstream transcription factors within the c-FOS promoter. Since the proteins of the FOS and Jun families of immediate-early genes dimerize to form activating protein (AP)-1, the present study was conducted to examine the expression of Jun transcription factors in schizophrenic and control subjects. Using Western blot analysis, we determined the protein levels of c-Jun, Jun B, and Jun D as well as the levels of c-jun mRNA by relative RT-PCR in post-mortem samples from cerebellar vermis. The expression of c-Jun protein and c-jun mRNA was significantly increased in the cerebellar vermis of patients with schizophrenia, whereas no significant differences were found in the expression of Jun B or Jun D proteins. Studies in rats indicated that the abnormal expression of c-Jun transcription factor observed in schizophrenic patients was not related to post-mortem intervals or chronic treatment with antipsychotic medications. This study provides new insights into cerebellar abnormalities of schizophrenia at the level of expression of c-Jun that target key genes associated with the MAP kinase cascade. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 34 | Life Sci. 2003 Jun 73: 801-11 |
| PMID | 12801600 |
| Title | Neurotensin: dual roles in psychostimulant and antipsychotic drug responses. |
| Abstract | Central administration of neurotensin (NT) results in a variety of neurobehavioral effects which, depending upon the administration site, resemble the effects of antipsychotic drugs (APDs) and psychostimulants. All clinically effective APDs exhibit significant affinities for dopamine D(2) receptors, supporting the hypothesis that an increase in dopaminergic tone contributes to schizophrenic symptoms. Psychostimulants increase extracellular dopamine (DA) levels and chronics administration can produce psychotic symptoms over time. APDs and psychostimulants induce FOS and NT expression in distinct striatal subregions, suggesting that changes in gene expression underlie some of their effects. To gain insight into the functions of NT, we analyzed APD and psychostimulant induction of FOS in NT knockout mice and rats pretreated with the NT antagonist SR 48692. In both NT knockout mice and rats pretreated with SR 48692, haloperidol-induced FOS expression was markedly attenuated in the dorsolateral striatum; amphetamine-induced FOS expression was reduced in the medial striatum. These results indicate that NT is required for the activation of specific subpopulations of striatal neurons in distinct striatal subregions in response to both APDs and psychostimulants. This review integrates these new findings with previous evidence implicating NT in both APD and psychostimulant responses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 35 | CNS Drug Rev 2003 -1 9: 375-88 |
| PMID | 14647530 |
| Title | Neuropharmacological profile of an atypical antipsychotic, NRA0562. |
| Abstract | schizophrenia is a serious and disabling psychiatric disorder affecting approximately 1% of the world's population. A new generation of atypical antipsychotics has been introduced over the past decade. These atypical antipsychotics have comparable or greater efficacy than traditional antipsychotics in the treatment of the psychotic symptoms of schizophrenia and a much improved neurologic side effect profile. This paper reviews the pharmacological efficacy and safety of a potential atypical antipsychotic, NRA0562. NRA0562 has a high affinity for dopamine D1, D2L, D4.2, 5-HT2A receptors as well as alpha1-adrenoceptors, and has a moderate affinity for H1 receptors. NRA0562 strongly binds to 5-HT2A receptors and alpha1-adrenoceptors in the frontal cortex, its binding to striatal D2 receptors is weaker, similar to that of clozapine. NRA562 displayed potent antipsychotic activities in animal models of schizophrenia, such as methamphetamine (MAP)-induced hyperactivity, apomorphine-induced disruption of pre-pulse inhibition and conditioned avoidance test. NRA0562 is more potent in reversing the inhibitory effects of MAP at A10 than at A9 dopamine neurons. It increased FOS-like immunoreactivity in the nucleus accumbens more effectively than in the dorsolateral striatum, indicating that NRA0562 has the profile of an atypical antipsychotic. In vivo assays for extrapyramidal side effect liability showed that NRA0562 has a low rate of neurological side effects. Thus, NRA0562 may have unique antipsychotic activity with a lower propensity for extrapyramidal side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 36 | Neuroscience 2003 -1 122: 739-45 |
| PMID | 14622917 |
| Title | Role of NR2B-containing N-methyl-D-aspartate receptors in haloperidol-induced c-Fos expression in the striatum and nucleus accumbens. |
| Abstract | Administration of haloperidol in rats leads to a robust induction of immediate-early genes including c-FOS throughout the striatum, which is significantly attenuated by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. The striatum expresses mainly NR1/NR2A and NR1/NR2B subtypes of NMDA receptors, each having different functional and pharmacological properties. In this study, rats were pretreated with Ro 25-6981, a selective antagonist for NR2B-containing NMDA receptors, in order to determine the relative contribution of this NMDA receptor subtype in NMDA-dependent haloperidol-induced c-FOS expression. Furthermore, to determine whether NMDA receptor subtype dependence of haloperidol-induced c-FOS expression is unique to the binding profile of haloperidol or whether it is a property of D2 receptor antagonism, the selective D2/D3 dopamine receptor antagonist, raclopride, was also used. Pretreatment with Ro 25-6981 led to a significant reduction in the number of nuclei showing c-FOS immunoreactivity in both the medial and lateral parts of the striatum. In the medial part of the striatum, this attenuation was almost as marked as that seen following pretreatment with MK-801; however, in the lateral part MK-801 pretreatment led to a significantly greater reduction in the number of c-FOS positive nuclei than did Ro 25-6981 pretreatment. This suggests that NR2B-containing NMDA receptors are involved in mediating most of the NMDA-dependent c-FOS expression in the medial striatum, but only responsible for mediating part of this induction in the lateral striatum. Furthermore, the pattern of attenuation of raclopride-induced c-FOS expression following Ro 25-6981 pretreatment was similar to that of haloperidol-induced c-FOS expression, indicating that the NMDA receptor subtype dependence of haloperidol-induced c-FOS expression is a property of D2 antagonism. The results indicate that NR2B-containing NMDA receptors are mainly involved in mediating haloperidol-induced c-FOS expression in the medial or "limbic" striatum, and suggest that NR2A-containing NMDA receptors may preferentially mediate haloperidol induced c-FOS expression in the lateral or "motor" striatum. This may have implications in the treatment of schizophrenia because co-administration of a selective blocker of NR2A-containing NMDA receptors may be able to reduce the severity of extrapyramidal motor symptoms caused by haloperidol treatment without interfering with its therapeutic effect that is presumably mediated via the medial part of the striatum. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 37 | J. Neurobiol. 2003 Oct 57: 67-80 |
| PMID | 12973829 |
| Title | Aberrant neuronal connectivity in CHL1-deficient mice is associated with altered information processing-related immediate early gene expression. |
| Abstract | In humans, loss or alteration of the CHL1/CALL gene may contribute to mental impairment associated with the 3p-syndrome, caused by distal deletions of the short (p) arm of chromosome 3, and schizophrenia. Mice deficient for the Close Homologue of L1 (CHL1) show aberrant connectivity of hippocampal mossy fibers and olfactory sensory axons, suggesting participation of CHL1 in the establishment of neuronal networks. Furthermore, behavioral studies showed that CHL1-deficient mice react differently towards novel experimental environments. These data raise the hypothesis that processing of information, possibly novel versus familiar, may be altered in the absence of CHL1. To test this hypothesis, brain activities were investigated after presentation of a novel, familiar, or neutral gustatory stimulus using metabolic mapping with ((14)C)-2-deoxyglucose (2-DG) and analysis of mRNA expression of the immediate early genes (IEGs) c-FOS and arg 3.1/arc by in situ hybridization. 2-DG labeling revealed only small differences between CHL1-deficient and wild-type littermate mice. In contrast, while the specific novelty-induced increase in c-FOS expression was maintained in most of the brain areas analyzed, c-FOS mRNA expression was similar after the novel and familiar taste in several brain areas of the CHL1-deficient mice. Furthermore, in these mutants, arg 3.1/arc expression was slightly reduced after the novel taste and increased after the familiar taste, leading to a similar arg 3.1/arc mRNA expression after both stimuli. Our results indicate that, in contrast to controls, CHL1-deficient mice might process novel and familiar information similarly and suggest that the altered neuronal connectivity in these mutants disturbs information processing at the molecular level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 38 | Neuropsychopharmacology 2003 Dec 28: 2064-76 |
| PMID | 12902994 |
| Title | SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile. |
| Abstract | SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced FOS immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 39 | Neuropharmacology 2003 Aug 45: 190-200 |
| PMID | 12842125 |
| Title | Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain. |
| Abstract | Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia, since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. The present study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-induced c-FOS expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), on c-FOS mRNA expression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesioned rats. In sham-lesioned rats, both haloperidol and olanzapine induced c-FOS expression in the caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol, increased c-FOS expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-induced c-FOS expression was markedly reduced in most areas. In contrast, the olanzapine-induced c-FOS expression was not altered in the nucleus accumbens shell and lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affect c-FOS expression in a compound- and regional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsychotic drugs in the context of an associated cortical pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 40 | Neuroscience 2003 -1 118: 297-310 |
| PMID | 12699766 |
| Title | Differential psychostimulant-induced activation of neural circuits in dopamine transporter knockout and wild type mice. |
| Abstract | Dopamine (DA) is a neurotransmitter that has been implicated in a wide variety of psychiatric disorders that include attention deficit-hyperactivity disorder (ADHD), schizophrenia, and drug abuse. Recently, we have been working with a mouse in which the gene for the DA transporter (DAT) has been disrupted. This mouse is hyperactive in the open field, displays an inability to inhibit ongoing behaviors, and is deficient on learning and memory tasks. Psychostimulants such as amphetamine and methylphenidate attenuate the hyperlocomotion of the mutants, but stimulate activity of the wild type (WT) controls. The objective of the present study is to examine the neural basis for the differential responses to psychostimulants in these mice. WT and DAT knockout (KO) animals were given vehicle or methylphenidate, amphetamine, or cocaine and brain sections were immunostained for FOS. In WT mice, methylphenidate induced FOS-like immunoreactivity (FOS-LI) in the mesostriatal and mesolimbocortical DA pathways that included the anterior olfactory nucleus, frontal association cortex, orbitofrontal cortex, cingulate cortex, caudate-putamen, globus pallidus, claustrum, lateral septum, nucleus accumbens, basolateral and central nuclei of the amygdala, bed nucleus of stria terminalis, subthalamic nucleus, substantia nigra, ventral tegmental area, and dorsal raphe. Additional areas of activation included the granular dentate gyrus, Edinger-Westphal nucleus, and periaqueductal gray. While the mutants showed little response in most of these same areas, the anterior olfactory nucleus, caudal caudate-putamen, lateral septum, basolateral and central nuclei of the amygdala, and bed nucleus of stria terminalis were activated. Amphetamine and cocaine produced similar changes to that for methylphenidate, except these psychostimulants also induced FOS-LI in the nucleus accumbens of the KO animals. Since the DAT gene is disrupted in the KO mouse, these findings suggest that dopaminergic mechanisms may mediate the WT responses, whereas non-dopaminergic systems predominate in the mutant. In the mutants, it appears that limbic areas and non-dopaminergic transmitter systems within these brain regions may mediate responses to psychostimulants. Inasmuch as the KO mouse may represent a useful animal model for ADHD and because psychostimulants such as cocaine are reinforcing to these animals, our results may provide some useful insights into the neural mechanisms-other than DA-that may contribute to the symptoms of ADHD and/or drug abuse in human patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 41 | Neuropharmacology 2003 Aug 45: 190-200 |
| PMID | 12842125 |
| Title | Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain. |
| Abstract | Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia, since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. The present study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-induced c-FOS expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), on c-FOS mRNA expression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesioned rats. In sham-lesioned rats, both haloperidol and olanzapine induced c-FOS expression in the caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol, increased c-FOS expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-induced c-FOS expression was markedly reduced in most areas. In contrast, the olanzapine-induced c-FOS expression was not altered in the nucleus accumbens shell and lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affect c-FOS expression in a compound- and regional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsychotic drugs in the context of an associated cortical pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 42 | Cell. Mol. Neurobiol. 2004 Dec 24: 769-80 |
| PMID | 15672679 |
| Title | Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia. |
| Abstract | 1. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists produce behavioral responses that closely resemble both positive and negative symptoms of schizophrenia. These drugs also induce excitatory and neurotoxic effects in limbic cortical areas. 2. We have here mapped the brain areas which show increased activity in response to noncompetitive NMDA-receptor antagonist administration concentrating especially to those brain areas that have been suggested to be relevant in the pathophysiology of schizophrenia. 3. Rats were treated intraperitoneally with a NMDA-receptor antagonist MK801 and activation of brain areas was detected by monitoring the expression of c-FOS mRNA by using in situ hybridization. 4. MK801 induced c-FOS mRNA expression of in the retrosplenial, entorhinal, and prefrontal cortices. Lower c-FOS expression was observed in the layer IV of the parietal and frontal cortex. In the thalamus, c-FOS mRNA expression was detected in the midline nuclei and in the reticular nucleus but not in the dorsomedial nucleus. In addition, c-FOS mRNA was expressed in the anterior olfactory nucleus, the ventral tegmental area, and in cerebellar granule neurons. 5. NMDA-receptor antagonist ketamine increased dopamine release in the parietal cortex, in the region where NMDA-receptor antagonist increased c-FOS mRNA expression. 6. Thus, the psychotropic NMDA-receptor antagonist induced c-FOS mRNA expression in most, but not all, brain areas implicated in the pathophysiology of schizophrenia. The high spatial resolution of in situ hybridization may help to define regions of interest for human imaging studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 43 | Neuropsychopharmacology 2004 Dec 29: 2180-8 |
| PMID | 15467708 |
| Title | Amphetamine-induced Fos is reduced in limbic cortical regions but not in the caudate or accumbens in a genetic model of NMDA receptor hypofunction. |
| Abstract | A mouse strain has been developed that expresses low levels of the NR1 subunit of the NMDA receptor. These mice are a model of chronic developmental NMDA receptor hypofunction and may therefore have relevance to the hypothesized NMDA receptor hypofunction in schizophrenia. Many schizophrenia patients show exaggerated behavioral and neuronal responses to amphetamine compared to healthy subjects. Studies were designed to determine if the NR1-deficient mice would exhibit enhanced sensitivity to amphetamine. Effects of amphetamine on behavioral activation and FOS induction were compared between the NR1-deficient mice and wild-type controls. The NR1 hypomorphic mice and controls exhibited similar locomotor activation after administration of amphetamine at 2 mg/kg. The mutant mice showed slightly reduced peak locomotor activity and slightly increased stereotypy after 4 mg/kg amphetamine. There were no differences in FOS induction in response to amphetamine in the caudate putamen, nucleus accumbens, medial or central amygdala nuclei, or bed nucleus of the stria terminalis. However, amphetamine-induced FOS was substantially attenuated in the medial frontal (infralimbic) and cingulate cortices, basolateral amygdala, and in the lateral septum of the mutant mice. The results suggest a neuroanatomically selective activation deficit to amphetamine challenge in the NR1-deficient mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 44 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2004 Sep 28: 997-1006 |
| PMID | 15380860 |
| Title | Differential expression of mitogen-activated protein kinases and immediate early genes fos and jun in thalamus in schizophrenia. |
| Abstract | Despite a growing body of evidence demonstrating that mitogen-activated protein (MAP) kinase pathways play an important physiological role in the CNS, little is known about their role and function in various mental disorders including schizophrenia. Our previous studies have shown increased expression of several intermediates of the extracellular signal-regulated (ERK) cascade and downstream transcription targets in cerebellar vermis without any changes in mesopontine tegmentum and Brodmann's area 10 in patients with schizophrenia. Given the evidence for abnormalities in schizophrenia in a neural circuit involving the cerebellum and thalamus, the present study was conducted to examine the expression of MAP kinases extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38, as well as immediate early genes FOS (c-FOS and FOS B) and jun (c-jun, jun B and jun D) using a Western blot analysis and reverse transcription polymerase chain reaction (RT-PCR) in postmortem thalamus from schizophrenic and control subjects. There were significant increase in ERK2, c-FOS and c-jun protein and mRNA levels in thalamus of patients with schizophrenia relative to controls. No statistically significant differences were found for ERK1, FOS B, Jun B or Jun D proteins in schizophrenic and control subjects. These results taken together with our previous findings provide new evidence for selective abnormalities of distinct MAP kinases and immediate early genes c-FOS and c-jun in a circuit involving the thalamus and cerebellum, which may contribute significantly to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 45 | Biol. Psychiatry 2004 Sep 56: 317-22 |
| PMID | 15336513 |
| Title | Increased neurogenesis in a rat ketamine model of schizophrenia. |
| Abstract | Growing evidence implicates abnormal neurodevelopment in schizophrenia, which manifests itself, for example, in reduced volume and cellular disarray of the hippocampus. This prompted us to investigate if there are indications of an altered neurodevelopment in this brain region. While neuron birth is largely completed by the end of gestation, granule neurons of the dentate gyrus are generated throughout life, thus offering an opportunity to investigate neurogenesis postnatally. We investigated whether repeated application of subanesthetic doses of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine, which has been shown to mimic model aspects of schizophrenia in animals, affects the hippocampal neurogenesis detected by bromodeoxyuridine incorporation. Cells were identified by immunocytochemistry. Subanesthetic doses of ketamine applied subchronically enhance neurogenesis in the hippocampal subgranular zone. In our animal model of schizophrenia, ketamine may evoke its stimulating effect on neurogenesis via a block of the N-methyl-D-aspartate receptor directly by reducing the c-FOS/c-Jun expression, resulting in a depression of the AP1 transcription factor complex and/or by a reduced nitric oxide production or an enhanced serotonergic activity. The newly formed neurons are not able to overcome the schizophrenia-related loss of parvalbumin expressing neurons and the behavioral abnormalities indicating that their functional integration is crucial. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 46 | Neuroscience 2004 -1 124: 33-42 |
| PMID | 14960337 |
| Title | A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamine-induced hyperactivity in rats: a role of inhibitory dopamine D(1/5) receptors in the prefrontal cortex? |
| Abstract | The behavioral and biochemical effects of the full dopamine D(1/5) receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg(-1), s.c.) and dihydrexidine (0-8.0 mg kg(-1), s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D(1/5) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 microg kg(-1), s.c.), but not by the selective dopamine D(2/3) receptor antagonist raclopride (0-25.0 microg kg(-1), s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg(-1), s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-FOS, showed that A 68930 and dihydrexidine caused a highly significant expression of c-FOS in the medial prefrontal cortex. This c-FOS expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-FOS expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D(1/5) receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D(1/5) receptors in schizophrenia, such inhibitory actions of dopamine D(1/5) receptor stimulation on psychomotor activation may have interesting clinical implications in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 47 | Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004 May 286: R927-34 |
| PMID | 14715495 |
| Title | Secretin depolarizes nucleus tractus solitarius neurons through activation of a nonselective cationic conductance. |
| Abstract | The recent suggestion that secretin may be useful in treating autism and schizophrenia has begun to focus attention on the mechanisms underlying this gut-brain peptide's actions in the central nervous system (CNS). In vitro autoradiographic localization of (125)I-secretin binding sites in rat brain shows the highest binding density in the nucleus tractus solitarius (NTS). Recent evidence suggests that intravenous infusion of secretin causes FOS activation in NTS, a relay station playing important roles in the central regulation of autonomic functions. In this study, whole cell patch-clamp recordings were obtained from 127 NTS neurons in rat medullary slices. The mean resting membrane potential of these neurons was -54.7 +/- 0.3 mV, the mean input resistance was 3.7 +/- 0.2 GOmega, and the action potential amplitude of these neurons was always >70 mV. Current-clamp studies showed that bath application of secretin depolarized the majority (80.8%; 42/52) of NTS neurons tested, whereas the remaining cells were either unaffected (17.3%; 9/52) or hyperpolarized (1.9%; 1/52). These depolarizing effects were maintained in the presence of 5 microM TTX and found to be concentration dependent from 10(-12) to 10(-7) M. Using voltage-clamp techniques, we also identified modulatory actions of secretin on specific ion channels. Our results demonstrate that while secretin is without effect on net whole cell potassium currents, it activates a nonselective cationic conductance (NSCC). These results show that NTS neurons are activated by secretin as a consequence of activation of a NSCC and support the emerging view that secretin can act as a neuropeptide within the CNS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 48 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2004 Sep 28: 997-1006 |
| PMID | 15380860 |
| Title | Differential expression of mitogen-activated protein kinases and immediate early genes fos and jun in thalamus in schizophrenia. |
| Abstract | Despite a growing body of evidence demonstrating that mitogen-activated protein (MAP) kinase pathways play an important physiological role in the CNS, little is known about their role and function in various mental disorders including schizophrenia. Our previous studies have shown increased expression of several intermediates of the extracellular signal-regulated (ERK) cascade and downstream transcription targets in cerebellar vermis without any changes in mesopontine tegmentum and Brodmann's area 10 in patients with schizophrenia. Given the evidence for abnormalities in schizophrenia in a neural circuit involving the cerebellum and thalamus, the present study was conducted to examine the expression of MAP kinases extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38, as well as immediate early genes FOS (c-FOS and FOS B) and jun (c-jun, jun B and jun D) using a Western blot analysis and reverse transcription polymerase chain reaction (RT-PCR) in postmortem thalamus from schizophrenic and control subjects. There were significant increase in ERK2, c-FOS and c-jun protein and mRNA levels in thalamus of patients with schizophrenia relative to controls. No statistically significant differences were found for ERK1, FOS B, Jun B or Jun D proteins in schizophrenic and control subjects. These results taken together with our previous findings provide new evidence for selective abnormalities of distinct MAP kinases and immediate early genes c-FOS and c-jun in a circuit involving the thalamus and cerebellum, which may contribute significantly to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 49 | Biol. Psychiatry 2005 May 57: 1138-46 |
| PMID | 15866553 |
| Title | Sensitized attentional performance and Fos-immunoreactive cholinergic neurons in the basal forebrain of amphetamine-pretreated rats. |
| Abstract | The consequences of repeated exposure to psychostimulants have been hypothesized to model aspects of schizophrenia. This experiment assessed the consequences of the administration of an escalating dosing regimen of amphetamine (AMPH) on attentional performance. FOS-like immunoreactivity (FOS-IR) in selected regions of these rats' brains was examined to test the hypothesis that AMPH-sensitized attentional impairments are associated with increased recruitment of basal forebrain cholinergic neurons. Rats were trained in a sustained attention task and then treated with saline or in accordance with an escalating dosing regimen of AMPH (1-10 mg/kg). Performance was assessed during the pretreatment and withdrawal periods and following the subsequent administration of AMPH "challenges" (.5, 1.0 mg/kg). Brain sections were double-immunostained to visualize FOS-IR and cholinergic neurons. Compared with the acute effects of AMPH, AMPH "challenges," administered over 2 months after the pretreatment was initiated, resulted in significant impairments in attentional performance. In AMPH-pretreated and -challenged animals, an increased number of FOS-IR neurons was observed in the basal forebrain. The majority of these neurons were cholinergic. The evidence supports the hypothesis that abnormally regulated cortical cholinergic inputs represent an integral component of neuronal models of the attentional dysfunctions of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 50 | Neuropsychopharmacology 2005 Feb 30: 261-7 |
| PMID | 15578005 |
| Title | Effects of l-stepholidine on forebrain Fos expression: comparison with clozapine and haloperidol. |
| Abstract | l-Stepholidine (SPD) is a tetrahydroprotoberberine alkaloid and a mixed dopamine D1 agonist/D2 antagonist. Preliminary clinical trials suggest that SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. Here, we report that SPD mimics the effect of the atypical antipsychotic drug clozapine, preferentially increasing FOS expression in corticolimbic areas. Thus, at 10 mg/kg (i.p.), SPD induced FOS expression in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral septal nucleus (LSN) without significantly affecting the dorsolateral striatum (DLSt). At higher doses (20-40 mg/kg), SPD also increased FOS expression in the DLSt. The increase, however, was less pronounced than the increase seen in the NAc. Within the NAc, SPD also induced more FOS expression in the shell than in the core. In all subcortical areas examined, the FOS expression induced by SPD was mimicked by the D2 antagonist sulpiride and reversed by the D2 agonist quinpirole, suggesting that the effect is due to blockade of D2-like receptors by SPD. In the mPFC, however, the effect was not mimicked by sulpride or reversed by quinpirole. It was also not mimicked by the D1 agonist SKF38393 or SKF38393 plus sulpride, and not reversed by the D1 antagonist SCH23390. These results suggest that, in the mPFC, SPD may induce FOS expression through a non-DA mechanism. Whether the mechanism involves an interaction of SPD with other neurotransmitters such as 5-HT and norepinephrine remains to be determined. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 51 | J. Pharmacol. Exp. Ther. 2005 Dec 315: 1265-77 |
| PMID | 16141369 |
| Title | Preclinical pharmacology of FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: a potential novel antipsychotic with lower histamine H1 receptor affinity than olanzapine. |
| Abstract | FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D2 (Ki= 6.3 nM), 5-HT(2A) (Ki= 7.3 nM), and 5-HT6 (Ki= 8.0 nM) human recombinant receptors and lower affinity for histamine H1 (Ki= 30 nM) and 5-HT2C (Ki= 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED200 = 6 mg/kg), blocked 5-HT2A agonist-induced increases in rat serum corticosterone levels (ED50= 1.8 mg/kg), and inhibited the ex vivo binding of [125I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT6 receptors (ED50= 10 mg/kg) but failed to inhibit ex vivo binding of [3H]pyrilamine to hypothalamic histamine H1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 (versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 (versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In FOS-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased FOS expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D2, 5-HT2A, and 5-HT6 receptors and a weak antagonist of H1 and 5-HT2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatment-emergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 52 | Neuropsychopharmacology 2005 Jul 30: 1324-33 |
| PMID | 15688082 |
| Title | Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists. |
| Abstract | N-methyl-D-aspartate (NMDA) receptor antagonists can elicit symptoms in humans that resemble those seen in schizophrenic patients. Rodents manifest locomotor and stereotypic behaviors when treated with NMDA receptor antagonists such as phencyclidine (PCP) or dizocilpine maleate (MK-801); these behaviors are usually associated with an activated dopamine system. However, recent evidence suggests that increased glutamatergic transmission mediates the effects of these NMDA receptor antagonists. The role of dopamine in PCP- and MK-801-induced behavior (eg hyperlocomotion) remains unclear. We used dopamine-deficient (DD) mice in which tyrosine hydroxylase is selectively inactivated in dopaminergic neurons to determine whether dopamine is required for the locomotor and molecular effects of PCP and MK-801. DD mice showed a similar increase in locomotor activity and c-FOS mRNA induction in the striatum in response to these NMDA receptor antagonists as control mice. Restoration of dopamine signaling in DD mice enhanced their locomotor response to PCP and MK-801. Administration of LY379268, a group II metabotropic glutamate receptor agonist that inhibits glutamate release, blocked PCP- and MK-801-induced hyperlocomotion in both DD and control mice. These results suggest that glutamate, rather than dopamine, is required for the locomotor and molecular effects of NMDA receptor antagonists, but that glutamate and dopamine can act cooperatively. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 53 | Eur. J. Pharmacol. 2006 Aug 544: 77-81 |
| PMID | 16860791 |
| Title | Subchronic administration of LY354740 does not modify ketamine-evoked behavior and neuronal activity in rats. |
| Abstract | Acute treatment with LY354740 {1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate}, a potent and selective agonist for group II metabotropic glutamate receptors (mGlu2/3), has previously been shown to block some schizophrenia-like effects of N-methyl-D-aspartate (NMDA) receptor antagonists, suggesting a novel therapeutic strategy for schizophrenia. The present study examined the effects of subchronic pretreatment with LY354740 (0.3, 3 and 10 mg/kg i.p.) on ketamine-evoked (12 mg/kg s.c.) prepulse inhibition deficits, hyperlocomotion and c-FOS expression. At all doses, LY354740 failed to reverse both behavioral and neuronal effects of the ketamine. These results therefore do not support the putative antipsychotic role of LY354740. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 54 | Brain Res. Bull. 2006 Apr 69: 338-45 |
| PMID | 16564431 |
| Title | Dose-response characteristics of ketamine effect on locomotion, cognitive function and central neuronal activity. |
| Abstract | The present dose-response study sought to determine the effects of subanesthetic dosages (4-16 mg/kg) of ketamine on locomotion, sensorimotor gating (PPI), working memory, as well as c-FOS expression in various limbic regions implicated in the pathogenesis of schizophrenia. In addition, we examined whether ketamine-induced locomotion was influenced by the dark/light cycle. We found that ketamine increased locomotor activity in a dose dependent manner, but found no influence of the dark-light cycle. Additionally, ketamine dose-dependently interrupted PPI, resulting in prepulse facilitation at doses of 8 and 12 mg/kg. The dose of 12 mg/kg also induced impairments in working memory assessed by the discrete-trial delayed-alternation task. C-FOS expression indicated that the dose-dependent behavioral effects of ketamine might be related to changes in the activity of limbic regions, notably hippocampus and amygdala. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 55 | Neurotox Res 2006 Dec 10: 199-209 |
| PMID | 17197370 |
| Title | Dopamine and incentive learning: a framework for considering antipsychotic medication effects. |
| Abstract | Hyperfunction of brain dopamine (DA) systems is associated with psychosis in schizophrenia and the medications used to treat schizophrenia are DA receptor blockers. DA also plays a critical role in incentive learning produced by rewarding stimuli. Using DA as the link, these results suggest that psychosis in schizophrenia can be understood from the point of view of excessive incentive learning. Incentive learning is mediated through the non-declarative memory system and may rely on the striatum or medial prefrontal cortex depending on the task. Typical and atypical antipsychotics differentially affect expression of the immediate early gene c-FOS, producing greater activity in the striatum and medial prefrontal cortex, respectively. This led to the hypothesis that performance of schizophrenic patients on tasks that depend on the striatum or medial prefrontal cortex will be differentially affected by their antipsychotic medication. Results from a number of published papers supported this dissociation. Furthermore, the effects of two atypical drugs, clozapine and olanzapine, on c-FOS expression were different from another atypical, risperidone that resembles the typical antipsychotics. Similarly, in tests of incentive learning, risperidone acted like the typical antipsychotics. Thus, typical and atypical antipsychotic drugs differed in the types of cognitive performance they affected and, furthermore, members of the atypical class differed in their effects on cognition. It remains the task of researchers and clinicians to sort out the symptoms associated with the endogenous illness from possible iatrogenic symptoms resulting from the antipsychotic medications used to treat schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 56 | Psychopharmacology (Berl.) 2006 Jan 184: 13-20 |
| PMID | 16328378 |
| Title | The effects of ziprasidone on regional c-Fos expression in the rat forebrain. |
| Abstract | Typical and atypical antipsychotic drugs produce characteristic patterns of immediate early gene expression in rat forebrain that are considered to reflect their effects in schizophrenia subjects. To use c-FOS immunohistochemistry to investigate the functional neuroanatomical profile of the newly introduced atypical agent ziprasidone. c-FOS immunohistochemistry was performed on paraformaldehyde-fixed cryosections of rat brains obtained, initially, from animals 2, 4, or 6 h after oral administration of 10 mg/kg ziprasidone or vehicle and, subsequently, from animals 2 h after oral administration of 1, 3, or 10 mg/kg ziprasidone or vehicle. The density of immunoreactive nuclei was assessed in pre-determined forebrain regions. Ziprasidone induced a time-dependent increase in the density of c-FOS-positive nuclei that was maximal at 2 h. At the 2 h time-point, c-FOS expression was significantly (p<0.05) elevated in the shell and core of the nucleus accumbens, lateral and medial caudate putamen, and lateral septum. At 4 h post-dose, c-FOS expression was also significantly increased in the cingulate gyrus. Ziprasidone-induced c-FOS expression was dose-dependent with significant (p<0.05) c-FOS expression observed in the nucleus accumbens (shell and core) and caudate putamen (lateral and medial) at 3 and 10 mg/kg and in the lateral septum at 10 mg/kg. Increased c-FOS expression in the nucleus accumbens and lateral septum is considered to be predictive of activity against positive symptoms, in the caudate putamen of motor side effect liability, and in the cingulate gyrus of efficacy against negative symptoms. Thus, the observed pattern of c-FOS expression induced in rat brain by ziprasidone is consistent with its reported clinical effects, namely, efficacy against positive symptoms with a therapeutic window over motor side effects and with some activity against negative symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 57 | Neuropharmacology 2006 Apr 50: 521-31 |
| PMID | 16324724 |
| Title | Dopamine D4 receptor signaling in the rat paraventricular hypothalamic nucleus: Evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation. |
| Abstract | The dopamine D4 receptor has been investigated for its potential role in several CNS disorders, notably schizophrenia and more recently, erectile dysfunction. Whereas studies have investigated dopamine D4 receptor-mediated signaling in vitro, there have been few, if any, attempts to identify dopamine D4 receptor signal transduction pathways in vivo. In the present studies, the selective dopamine D4 agonist PD168077 induces c-FOS expression and extracellular signal regulated kinase (ERK) phosphorylation in the hypothalamic paraventricular nucleus (PVN), a site known to regulate proerectile activity. The selective dopamine D4 receptor antagonist A-381393 blocked both c-FOS expression and ERK1/2 phosphorylation produced by PD168077. In addition, PD168077-induced ERK1/2 phosphorylation was prevented by SL327, an inhibitor of ERK1/2 phosphorylation. Interestingly, treatment with A-381393 alone significantly reduced the amount of FOS immunoreactivity as compared to basal expression observed in vehicle-treated controls. Dopamine D4 receptor and c-FOS coexpression in the PVN was observed using double immunohistochemical labeling, suggesting that PD168077-induced signaling may result from direct dopamine D4 receptor activation. Our results demonstrate functional dopamine D4 receptor expression and natural coupling in the PVN linked to signal transduction pathways that include immediate early gene and MAP kinase activation. Further, the ability of the selective dopamine D4 antagonist A-381393 alone to reduce c-FOS expression below control levels may imply the presence of a tonic dopamine D4 receptor activation under basal conditions in vivo. These findings provide additional evidence that the PVN may be a site of dopamine D4 receptor-mediated proerectile activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 58 | Neurotox Res 2006 Dec 10: 199-209 |
| PMID | 17197370 |
| Title | Dopamine and incentive learning: a framework for considering antipsychotic medication effects. |
| Abstract | Hyperfunction of brain dopamine (DA) systems is associated with psychosis in schizophrenia and the medications used to treat schizophrenia are DA receptor blockers. DA also plays a critical role in incentive learning produced by rewarding stimuli. Using DA as the link, these results suggest that psychosis in schizophrenia can be understood from the point of view of excessive incentive learning. Incentive learning is mediated through the non-declarative memory system and may rely on the striatum or medial prefrontal cortex depending on the task. Typical and atypical antipsychotics differentially affect expression of the immediate early gene c-FOS, producing greater activity in the striatum and medial prefrontal cortex, respectively. This led to the hypothesis that performance of schizophrenic patients on tasks that depend on the striatum or medial prefrontal cortex will be differentially affected by their antipsychotic medication. Results from a number of published papers supported this dissociation. Furthermore, the effects of two atypical drugs, clozapine and olanzapine, on c-FOS expression were different from another atypical, risperidone that resembles the typical antipsychotics. Similarly, in tests of incentive learning, risperidone acted like the typical antipsychotics. Thus, typical and atypical antipsychotic drugs differed in the types of cognitive performance they affected and, furthermore, members of the atypical class differed in their effects on cognition. It remains the task of researchers and clinicians to sort out the symptoms associated with the endogenous illness from possible iatrogenic symptoms resulting from the antipsychotic medications used to treat schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 59 | Schizophr. Res. 2007 Aug 94: 128-38 |
| PMID | 17560766 |
| Title | Schizophrenic patients treated with clozapine or olanzapine perform better on theory of mind tasks than those treated with risperidone or typical antipsychotic medications. |
| Abstract | Theory of mind (ToM), the ability to attribute mental states to others, is associated with medial prefrontal cortical (mPFC) activity and is impaired in schizophrenia. Olanzapine or clozapine but not typical antipsychotics or risperidone preferentially affect c-FOS expression in mPFC in animals. We tested the hypothesis that schizophrenic patients treated with different antipsychotics would perform differently on ToM tasks. Groups receiving Typicals (n=23), Clozapine (n=18), Olanzapine (n=20) or Risperidone (n=23) and a Control group of healthy volunteers (n=24) were matched for age, gender, handedness and education. ToM functioning was assessed with picture sequence, second-order belief and faux-pas tests. schizophrenic groups performed similarly to controls on non-ToM conditions. The Olanzapine and Clozapine groups performed similarly to Controls on ToM tasks. The Typicals and Risperidone groups performed worse than the other groups on ToM tasks. We concluded that ToM performance of schizophrenic patients is influenced by the antipsychotic they are taking. Our results suggest that olanzapine or clozapine but not typicals or risperidone may improve or protect ToM ability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 60 | Neuropharmacology 2007 Jun 52: 1671-7 |
| PMID | 17493641 |
| Title | Role of G(q) protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. |
| Abstract | Extensive evidence suggests that 5-HT2 receptors may play a role in mental disorders including schizophrenia. In addition, several studies indicate that G(q)-coupled 5-HT(2A) receptors are likely targets for the initiation of events leading to the hallucinogenic behavior elicited by lysergic acid diethylamide (LSD), (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and related drugs. However, 5-HT(2A) receptors couple to other G proteins in addition to G(q) protein. To evaluate the role of the G(q) signaling pathway in DOI-induced behaviors, we utilized two behavioral models of 5-HT(2A) receptor activation: induction of head-twitches by DOI, a common response to hallucinogenic drugs in rodents, and DOI elicited anxiolytic-like effects in the elevated plus maze. Experimental subjects were genetically modified mice [Galpha(q)(-/-)] in which the G(q) alpha gene was eliminated. Galpha(q)(-/-) mice exhibited a decrease in DOI-induced head-twitches, when compared to wild-type littermates. In addition, the DOI-induced increase in anxiolytic-like behavior was abolished in Galpha(q)(-/-) mice. These results, combined with our finding that DOI-induced FOS expression in the medial prefrontal cortex was also eliminated in Galpha(q)(-/-) mice, suggests a key role for G(q) protein in hallucinogenic drug effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 61 | Schizophr. Res. 2007 Aug 94: 128-38 |
| PMID | 17560766 |
| Title | Schizophrenic patients treated with clozapine or olanzapine perform better on theory of mind tasks than those treated with risperidone or typical antipsychotic medications. |
| Abstract | Theory of mind (ToM), the ability to attribute mental states to others, is associated with medial prefrontal cortical (mPFC) activity and is impaired in schizophrenia. Olanzapine or clozapine but not typical antipsychotics or risperidone preferentially affect c-FOS expression in mPFC in animals. We tested the hypothesis that schizophrenic patients treated with different antipsychotics would perform differently on ToM tasks. Groups receiving Typicals (n=23), Clozapine (n=18), Olanzapine (n=20) or Risperidone (n=23) and a Control group of healthy volunteers (n=24) were matched for age, gender, handedness and education. ToM functioning was assessed with picture sequence, second-order belief and faux-pas tests. schizophrenic groups performed similarly to controls on non-ToM conditions. The Olanzapine and Clozapine groups performed similarly to Controls on ToM tasks. The Typicals and Risperidone groups performed worse than the other groups on ToM tasks. We concluded that ToM performance of schizophrenic patients is influenced by the antipsychotic they are taking. Our results suggest that olanzapine or clozapine but not typicals or risperidone may improve or protect ToM ability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 62 | Neuroscience 2007 Nov 149: 861-70 |
| PMID | 17905522 |
| Title | Heterozygous neuregulin 1 mice display greater baseline and Delta(9)-tetrahydrocannabinol-induced c-Fos expression. |
| Abstract | Cannabis use may increase the risk of developing schizophrenia by precipitating the disorder in genetically vulnerable individuals. Neuregulin 1 (NRG1) is a schizophrenia susceptibility gene and mutant mice heterozygous for the transmembrane domain of this gene (Nrg1 HET mice) exhibit a schizophrenia-related phenotype. We have recently shown that Nrg1 HET mice are more sensitive to the behavioral effects of the main psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC). In the present study, we examined the effects of THC (10 mg/kg i.p.) on neuronal activity in Nrg1 HET mice and wild type-like (WT) mice using c-FOS immunohistochemistry. In the lateral septum, THC selectively increased c-FOS expression in Nrg1 HET mice with no corresponding effect being observed in WT mice. In addition, THC promoted a greater increase in c-FOS expression in Nrg1 HET mice than WT mice in the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. Consistent with Nrg1 HET mice exhibiting a schizophrenia-related phenotype, these mice expressed greater drug-free levels of c-FOS in two regions thought to be involved in schizophrenia, the shell of the nucleus accumbens and the lateral septum. Interestingly, the effects of genotype on c-FOS expression, drug-free or following THC exposure, were only observed when animals experienced behavioral testing prior to perfusion. This suggests an interaction with stress was necessary for the promotion of these effects. These data provide neurobiological correlates for the enhanced behavioral sensitivity of Nrg1 HET mice to THC and reinforce the existence of cannabinoid-neuregulin 1 interactions in the CNS. This research may enhance our understanding of how genetic factors increase individual vulnerability to schizophrenia and cannabis-induced psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 63 | Proc. Natl. Acad. Sci. U.S.A. 2007 Sep 104: 14843-8 |
| PMID | 17785415 |
| Title | Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. |
| Abstract | NMDA receptor (NMDA-R) antagonists are extensively used as schizophrenia models because of their ability to evoke positive and negative symptoms as well as cognitive deficits similar to those of the illness. Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. These deficits are of particular interest because an early improvement in cognitive performance predicts a better long-term clinical outcome. Here, we examined the effect of the noncompetitive NMDA-R antagonist phencyclidine (PCP) on PFC function to understand the cellular and network elements involved in its schizomimetic actions. PCP induces a marked disruption of the activity of the PFC in the rat, increasing and decreasing the activity of 45% and 33% of the pyramidal neurons recorded, respectively (22% of the neurons were unaffected). Concurrently, PCP markedly reduced cortical synchrony in the delta frequency range (0.3-4 Hz) as assessed by recording local field potentials. The subsequent administration of the antipsychotic drugs haloperidol and clozapine reversed PCP effects on pyramidal cell firing and cortical synchronization. PCP increased c-FOS expression in PFC pyramidal neurons, an effect prevented by the administration of clozapine. PCP also enhanced c-FOS expression in the centromedial and mediodorsal (but not reticular) nuclei of the thalamus, suggesting the participation of enhanced thalamocortical excitatory inputs. These results shed light on the involvement of PFC in the schizomimetic action of NMDA-R antagonists and show that antipsychotic drugs may partly exert their therapeutic effect by normalizing a disrupted PFC activity, an effect that may add to subcortical dopamine receptor blockade. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 64 | Pharmacol. Biochem. Behav. 2007 Nov 88: 73-81 |
| PMID | 17698179 |
| Title | Subchronic phencyclidine exposure potentiates the behavioral and c-Fos response to stressful stimuli in rats. |
| Abstract | Prior exposure to subchronic phencyclidine (PCP) produces behaviors argued to model schizophrenia in rats, including alterations in the behavioral responses to stress-inducing stimuli. Prior exposure to a single injection of PCP also produces a number of schizophrenia-like behaviors in rats, suggesting that a single injection of PCP is able to model schizophrenia-like behaviors as well. We examined the effects of prior exposure to either a single injection or subchronic PCP on stress-induced behavior and c-FOS-like immunoreactivity (FLI). Twenty-four hours after a single injection of PCP (15 mg/kg) or subchronic PCP (10 mg/kg for 14 days) or saline, male rats were exposed to either novel environment, forced swim, or left in their home cages. A single injection of PCP produced only small effects on stress-induced behavior and FLI: a drugxtime interaction on the number of cage crossings in the novel environment and a drugxcondition interaction on FLI in the shell of the nucleus accumbens. However, subchronic PCP decreased cage crosses and rears in the novel environment and increased immobility in the forced swim test. The increased immobility in the forced swim test was accompanied by increased striatal FLI. These data suggest that while a single injection of PCP produces only minimal alterations in the response to stressful stimuli, subchronic PCP produces a quantitatively greater effect. In addition, the observation that PCP pretreatment increased striatal FLI induced by forced swim but not novelty suggest that PCP alters the behavioral responses to these stressors via different neurochemical mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 65 | Mol. Pharmacol. 2007 Aug 72: 477-84 |
| PMID | 17526600 |
| Title | A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. |
| Abstract | Recent clinical studies reveal that selective agonists of group II metabotropic glutamate (mGlu) receptors have robust efficacy in treating positive and negative symptoms in patients with schizophrenia. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs and reduce the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. Because increased excitation of the medial prefrontal cortex (mPFC) has been implicated in pathophysiology of schizophrenia, the ability of group II mGlu receptor agonists to reduce hallucinogenic drug action in this region is believed to be directly related to their antipsychotic efficacy. A novel class of ligands, termed positive allosteric modulators, has recently been identified, displaying exceptional mGlu2 receptor selectivity. These compounds do not activate mGlu2 receptors directly but potentiate the ability of glutamate and other agonists to activate this receptor. We now report that the mGlu2 receptor-selective positive allosteric modulator biphenyl-indanone A (BINA) modulates excitatory neurotransmission in the mPFC and attenuates the in vivo actions of the hallucinogenic 5-HT(2A/2C) receptor agonist (-)2,5-dimethoxy-4-bromoamphetamine [(-)DOB]. BINA attenuates serotonin-induced increases in spontaneous excitatory postsynaptic currents in the mPFC, mimicking the effect of the mGlu2/3 receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV). In addition, BINA reduced (-)DOB-induced head twitch behavior and FOS expression in mPFC, effects reversed by pretreatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl) -3 - (xanth-9-yl-)propionic acid (LY341495). These data confirm the relevance of excitatory signaling in the mPFC to the behavioral actions of hallucinogens and further support the targeting of mGlu2 receptors as a novel strategy for treating glutamatergic dysfunction in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 66 | J. Neurosci. Res. 2007 Jun 85: 1810-8 |
| PMID | 17455307 |
| Title | Alpha-7 nicotinic acetylcholine receptor agonists selectively activate limbic regions of the rat forebrain: an effect similar to antipsychotics. |
| Abstract | It is considered that activation of nicotinic alpha7 receptors (alpha7 nAChR) is useful for the treatment of cognitive disturbances in schizophrenia and Alzheimer's disease. Recently, selective alpha7 nAChR agonists have been discovered and are used to validate the alpha7 nAChR as a drug target for the treatment of cognitive disturbances in schizophrenia. One important feature shared by all known antipsychotics is their capacity to induce expression of the neuronal immediate-early gene c-FOS in the limbic forebrain. Using two novel and selective alpha7 nAChR agonists, PNU-282987 and SSR180711, we investigated their ability to induce c-FOS expression in the limbic forebrain with particular emphasis on the same regions reported to be activated by antipsychotics. Both alpha7 nAChR agonists increased c-FOS dose-dependently in the prefrontal cortex and the shell of nucleus accumbens, while leaving the core of nucleus accumbens and the dorsolateral striatum unaffected. The accumbal and cortical effect of SSR180711 was blocked completely by pre-administration of the alpha7 nAChR antagonist methyllycaconitine. Also, SSR180711 displayed no c-FOS-inducing effect in alpha7 nAChR knock-out mice. In conclusion, these results show that selective pharmacologic stimulation of alpha7 nAChR function results in activation of forebrain regions similar to conventional antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 67 | Brain Res. 2007 May 1149: 50-7 |
| PMID | 17382304 |
| Title | Effect of the selective dopamine D3 receptor antagonist SB-277011-A on regional c-Fos-like expression in rat forebrain. |
| Abstract | SB-277011-A is a dopamine D(3) receptor antagonist that exhibits over 100-fold selectivity over dopamine D(2) receptors and a broad spectrum of other receptor, ion channels, and enzymes. We employed c-FOS immunohistochemistry to characterise the functional neuroanatomical effects of acute administration of SB-277011-A and observed a time-dependent increase in the density of c-FOS-like positive nuclei in rat forebrain with maximal effects observed 2 h post-dose. The relative influence of the different brain regions on the overall effect of SB-277011-A was ranked by partial least squares discriminant analysis loadings plot which indicated that sites within the nucleus accumbens exerted the greatest influence on the separation of the vehicle and SB-277011-A treatment groups. At the 2 h time-point, c-FOS-like expression was shown to be significantly elevated (p<0.05) in the core and shell of the nucleus accumbens, at both rostral and caudal levels, and in the lateral septum. No significant changes were detected in the caudate nucleus (lateral or medial) or in the cingulate, infralimbic prefrontal, or somatosensory cortices. The capacity of SB-277011-A to trigger immediate early gene expression in these limbic regions of rat brain adds to a growing consensus of the potential utility of dopamine D(3) receptor antagonism in psychiatric disorders including schizophrenia and drug dependency. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 68 | Psychopharmacology (Berl.) 2007 Apr 191: 297-310 |
| PMID | 17225165 |
| Title | Propranolol blocks chronic risperidone treatment-induced enhancement of spatial working memory performance of rats in a delayed matching-to-place water maze task. |
| Abstract | Atypical antipsychotics improve cognitive function, including working memory, in schizophrenia. Some atypical antipsychotics have been reported to activate the locus coeruleus and induce beta-adrenoceptor antagonist sensitive c-FOS-like immunoreactivity in the prefrontal cortex. The present study investigated the effects of chronic treatment of rats with risperidone (1 mg kg(-1) day(-1) s.c.), clozapine (10 mg kg(-1) day(-1) s.c.), or acidified saline vehicle control for 2, 4, or 8 weeks on spatial working memory performance in a delayed matching-to-place water maze task with a 60-s inter-trial retention interval with and without acute challenge with propranolol (10 mg/kg i.p.). Treatment with risperidone for 8 weeks, but not 2 or 4 weeks, significantly improved working memory performance. In contrast, treatment with clozapine for up to 8 weeks did not improve working memory. Acute challenge with propranolol blocked the improvement in working memory produced by chronic treatment with risperidone, but had no significant effect on performance in saline- or clozapine-treated animals. The delayed matching-to-place water maze task may prove valuable in the investigation of the behavioural pharmacology of the cognitive effects of antipsychotic drugs. These data suggest that beta adrenoceptors may contribute to the cognitive effects of chronic treatment with atypical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 69 | J. Psychopharmacol. (Oxford) 2008 Jul 22: 536-42 |
| PMID | 18208916 |
| Title | Differential expression of IEG mRNA in rat brain following acute treatment with clozapine or haloperidol: a semi-quantitative RT-PCR study. |
| Abstract | Antipsychotic drugs have been shown to modulate immediate early gene (IEG) expression in rat brain regions that are associated with schizophrenia, which may be directly linked to their immediate therapeutic benefit. In this study, we analysed the expression profile of a series of IEGs (c-FOS, c-jun, fra-1, Krox-20, Krox-24, arc, sgk-1, BDNF and NARP) in six rat brain regions (prefrontal cortex, hippocampus, striatum, nucleus accumbens, thalamus and cerebellum). Rats (n=5) were administered either clozapine (20 mg/kg i.p.), haloperidol (1 mg/kg i.p.) or the appropriate vehicle with pre-treatment times of 1, 6 and 24 h. IEG expression was analysed in these regions by Taqman RT-PCR. The spatial and temporal profile of IEG induction following antipsychotic drug treatment correlates with regions associated with the efficacy and side effect profile of each drug. In particular, sgk-1 expression levels after antipsychotic drug treatment may have predictive value when investigating the profile of a novel antipsychotic drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 70 | Hippocampus 2008 -1 18: 169-81 |
| PMID | 17960646 |
| Title | The amygdala modulates neuronal activation in the hippocampus in response to spatial novelty. |
| Abstract | Emerging evidence indicates that the amygdala and the hippocampus play an important role in the pathophysiology of major psychotic disorders. Consistent with this evidence, and with data indicating amygdala modulation of hippocampal activity, animal model investigations have shown that a disruption of amygdala activity induces neurochemical changes in the hippocampus that are similar to those detected in subjects with schizophrenia. With the present study, we used induction of the immediate early gene FOS, to test the hypothesis that the amygdala may affect neuronal activation of the hippocampus in response to different spatial environments (familiar, modified, and novel). Exploratory and anxiety related behaviors were also assessed. In vehicle-treated rats, exposure to a modified version of the familiar environment was associated with an increase of numerical densities of FOS-immunoreactive nuclei in sectors CA1 and CA2, while exposure to a completely novel environment was associated with an increase in sectors CA1, CA4, and DG, compared with the familiar environment. Pharmacological disruption of amygdala activity resulted in a failure to increase FOS induction in the hippocampus in response to these environments. Exploratory behavior in response to the different environments was not altered by manipulation of amygdala activity. These findings support the idea that the amygdala modulates spatial information processing in the hippocampus and may affect encoding of specific environmental features, while complex behavioral responses to environment may be the result of broader neural circuits. These findings also raise the possibility that amygdala abnormalities may contribute to impairments in cognitive information processing in subjects with major psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 71 | Neurotox Res 2008 Oct 14: 129-40 |
| PMID | 19073421 |
| Title | NMDA antagonist and antipsychotic actions in cortico-subcortical circuits. |
| Abstract | Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. schizophrenic patients show a reduced performance in tasks engaging the PFC and a reduction of markers of cellular integrity and function. Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to exacerbate schizophrenia symptoms in patients and to elicit psychotomimetic actions in healthy volunteers. Also, these drugs evoke behavioral alterations in experimental animals that resemble schizophrenia symptoms. The PFC seems to be a key target area for these agents. However, the cellular and network elements involved are poorly known. Cognitive deficits are of particular interest since an early antipsychotic-induced improvement in cognitive performance predicts a better long-term clinical outcome. Here we report that the non-competitive NMDA receptor antagonist phencyclidine (PCP) induces a marked disruption of the activity of PFC. PCP administration increased the activity of a substantial proportion of pyramidal neurons, as evidenced by an increase in discharge rate and in c-FOS expression. Examination of the effects of PCP on other brain areas revealed an increased c-FOS expression in a number of cortical and subcortical areas, but notably in thalamic nuclei projecting to the PFC. The administration of classical (haloperidol) and/or atypical (clozapine) antipsychotic drugs reversed PCP effects. These results indicate that PCP induces a marked disruption of the network activity in PFC and that antipsychotic drugs may partly exert their therapeutic effect by normalizing hyperactive cortico-thalamocortical circuits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 72 | Mol Brain 2008 -1 1: 6 |
| PMID | 18803808 |
| Title | Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. |
| Abstract | Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-FOS expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 73 | Psychopharmacology (Berl.) 2008 Aug 199: 275-89 |
| PMID | 18521575 |
| Title | The antipsychotic potential of l-stepholidine--a naturally occurring dopamine receptor D1 agonist and D2 antagonist. |
| Abstract | l-Stepholidine, a dopamine D(2) antagonist with D(1) agonist activity, should in theory control psychosis and treat cognitive symptoms by enhancing cortical dopamine transmission. Though several articles describe its impact on the dopamine system, it has not been systematically evaluated and compared to available antipsychotics. We examined its in vitro interaction with dopamine D(2) and D(1) receptors and compared its in vivo pharmacokinetic profile to haloperidol (typical) and clozapine (atypical) in animal models predictive of antipsychotic activity. In vitro, l-stepholidine showed significant activity on dopamine receptors, and in vivo, l-stepholidine demonstrated a dose-dependent striatal receptor occupancy (RO) at D(1) and D(2) receptors (D(1) 9-77%, 0.3-30 mg/kg; D(2) 44-94%, 1-30 mg/kg), though it showed a rather rapid decline of D(2) occupancy related to its quick elimination. In tests of antipsychotic efficacy, it was effective in reducing amphetamine- and phencyclidine-induced locomotion as well as conditioned avoidance response, whereas catalepsy and prolactin elevation, the main side effects, appeared only at high D(2)RO (>80%). This preferential therapeutic profile was supported by a preferential immediate early gene (FOS) induction in the nucleus accumbens over dorsolateral striatum. We confirmed its D(1) agonism in vitro, and then using D(2) receptor, knockout mice showed that l-stepholidine shows D(1) agonism in the therapeutic dose range. Thus, l-stepholidine shows efficacy like an "atypical" antipsychotic in traditional animal models predictive of antipsychotic activity and shows in vitro and in vivo D(1) agonism, and, if its rapid elimination does not limit its actions, it could provide a unique therapeutic approach to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 74 | Neuroscience 2008 Jun 154: 741-53 |
| PMID | 18495359 |
| Title | The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain: Differential effects in the juvenile and adult rat. |
| Abstract | Due to the cognitive-enhancing properties of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists, they have attracted interest for the treatment of cognitive disturbances in schizophrenia. schizophrenia typically presents in late adolescence or early adulthood. It is therefore important to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile and adult rat forebrain using two markers, activity-regulated cytoskeleton-associated protein (Arc) and c-FOS, to map neuronal activity. Acute administration of A-582941 (1, 3, 10 mg/kg) induced a dose-dependent increase in Arc mRNA expression in the medial prefrontal cortex (mPFC) and the ventral/lateral orbitofrontal (VO/LO) cortex of juvenile, but not adult rats. This effect was mitigated by the alpha7 nAChR antagonist methyllycaconitine. A-582941 also increased c-FOS mRNA expression in the mPFC of juvenile, but not adult rats. Furthermore, A-582941 increased the number of Arc and c-FOS immunopositive cells in the mPFC, VO/LO, and shell of the nucleus accumbens, in both juvenile and adult rats. The A-582941-induced c-FOS protein expression was significantly greater in the mPFC and VO/LO of juvenile compared with adult rats. These data indicate that A-582941-induced alpha7 nAChR stimulation activates brain regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 75 | Neuropsychopharmacology 2008 Dec 33: 3164-75 |
| PMID | 18354384 |
| Title | Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen. |
| Abstract | We have previously demonstrated that pallidotegmental GABAergic neurons play a crucial role in prepulse inhibition (PPI) of the startle reflex in mice through the activation of GABA(B) receptors in pedunculopontine tegmental neurons. In this study, we investigated whether PPI disruption induced by methamphetamine (METH) or MK-801 is associated with the dysfunction of pallidotegmental neurons. Furthermore, we examined the effects of baclofen, a GABA(B) receptor agonist, on METH- and MK-801-induced PPI impairment. Acute treatment with METH (3 mg/kg, subcutaneouly (s.c.)) and MK-801 (>0.3 mg/kg, s.c.) significantly disrupted PPI, accompanied by the suppression of c-FOS expression in lateral globus pallidus induced by PPI. Furthermore, acute treatment with METH and MK-801 stimulated c-FOS expression in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPT test, although PPI alone had no effect on c-FOS expression. Repeated treatment with 1 mg/kg METH for 7 days, which did not affect PPI acutely, showed similar effects on PPI and c-FOS expression to acute treatment with METH (3 mg/kg). Baclofen dose-dependently ameliorated PPI impairment induced by acute treatment with METH (3 mg/kg) and MK-801 (1 mg/kg), and decreased METH- and MK-801-stimulated c-FOS expression in PnC to the basal level. These results suggest that dysfunction of pallidotegmental neurons is involved in PPI disruption caused by METH and MK-801 in mice. GABA(B) receptor may constitute a putative target in treating neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia and METH psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 76 | Synapse 2008 Feb 62: 128-36 |
| PMID | 18000809 |
| Title | Behavioral and biochemical responses to d-amphetamine in MCH1 receptor knockout mice. |
| Abstract | The melanin-concentrating hormone (MCH) system is anatomically and functionally interlaced with the mesocorticolimbic dopamine system. Therefore, we investigated whether MCH(1) receptor knockout (KO) mice are more susceptible than wild-type (WT) mice to psychostimulant-induced locomotor stimulation and sensitization, dopamine receptor-mediated phosphorylation events and c-FOS expression within the frontal cortex and ventral striatum. MCH(1) receptor KO mice have 20% higher basal locomotor activity, are hypersensitive to the locomotor activating effects of d-amphetamine (1 mg/kg), and develop behavioral sensitization to a regimen of repeated d-amphetamine administration that does not induce sensitization in WT mice. In addition, d-amphetamine-mediated regulation of p44-mitogen activated protein kinase (MAPK) phosphorylation within the frontal cortex was significantly enhanced in MCH(1) receptor KO mice, when compared with WT mice. No significant genotype difference in the effects of d-amphetamine on MAPK phosphorylation events within the ventral striatum, phosphorylation at Ser(897) of the NR1 subunit of the NMDA receptor or Ca(2+) and cyclic AMP response-element binding-protein (CREB) at Ser(133) in the frontal cortex was detected. d-Amphetamine (3 mg/kg) increased c-FOS expression within the frontal cortex in MCH(1) receptor KO mice, but not WT mice. There were no d-amphetamine-induced changes in c-FOS expression within the ventromedial striatum in KO or WT mice. Overall, MCH(1) receptor KO mice are hypersensitive to the behavioral and molecular effects of the dopaminergic psychostimulant d-amphetamine. Increased frontal cortical MAPK phosphorylation and c-FOS expression in MCH(1) receptor KO mice indicates that the MCH(1) receptor may be an important target for treating neuropsychiatric disorders characterized by frontal cortex dysfunction, including depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 77 | Pharmacol. Biochem. Behav. 2008 Jan 88: 291-8 |
| PMID | 17920665 |
| Title | 5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine. |
| Abstract | 5-HT6 receptors have been implicated in consolidation of visuospatial and reward-based learning tasks. Since 5-HT6 receptors may be important in modulation of sensory gating which is often affected in schizophrenic patients, we tested whether Ro 4368554, a 5-HT6 selective antagonist at a dose of 10 mg/kg, could reverse the loss of prepulse inhibition from apomorphine or scopolamine. In addition, we also tested whether Ro 4368554 altered fear conditioning using fear potentiated startle, a model for emotional learning. Prepulse inhibition of startle was disrupted by apomorphine (0.5 mg/kg) when prepulse emissions were 5 dB above background but not above 15 dB, while scopolamine (0.5 mg/kg) caused disruption at both prepulse levels. Scopolamine-mediated disruption was not reversed by Ro 4368854 but apomorphine-mediated disruption was significantly ameliorated by 5-HT6 inhibition. For fear potentiated startle, scopolamine and/or Ro 4368554 were administered before two daily fear conditioning sessions; rats were tested on the following day. Rats that received scopolamine displayed no fear potentiated startle but Ro 4368554 reversed this scopolamine deficit. Additionally, we mapped FOS induction in rats treated with scopolamine and/or Ro 4368554; scopolamine increased FOS expression in the central nucleus of the amygdala and this was attenuated by Ro 4368554. In summary, we have demonstrated the efficacy of 5-HT6 antagonists in modulating sensory gating and fear conditioning, and thus may be of therapeutic use for schizophrenia-related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 78 | Neurotox Res 2008 Oct 14: 129-40 |
| PMID | 19073421 |
| Title | NMDA antagonist and antipsychotic actions in cortico-subcortical circuits. |
| Abstract | Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. schizophrenic patients show a reduced performance in tasks engaging the PFC and a reduction of markers of cellular integrity and function. Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to exacerbate schizophrenia symptoms in patients and to elicit psychotomimetic actions in healthy volunteers. Also, these drugs evoke behavioral alterations in experimental animals that resemble schizophrenia symptoms. The PFC seems to be a key target area for these agents. However, the cellular and network elements involved are poorly known. Cognitive deficits are of particular interest since an early antipsychotic-induced improvement in cognitive performance predicts a better long-term clinical outcome. Here we report that the non-competitive NMDA receptor antagonist phencyclidine (PCP) induces a marked disruption of the activity of PFC. PCP administration increased the activity of a substantial proportion of pyramidal neurons, as evidenced by an increase in discharge rate and in c-FOS expression. Examination of the effects of PCP on other brain areas revealed an increased c-FOS expression in a number of cortical and subcortical areas, but notably in thalamic nuclei projecting to the PFC. The administration of classical (haloperidol) and/or atypical (clozapine) antipsychotic drugs reversed PCP effects. These results indicate that PCP induces a marked disruption of the network activity in PFC and that antipsychotic drugs may partly exert their therapeutic effect by normalizing hyperactive cortico-thalamocortical circuits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 79 | Mol Brain 2008 -1 1: 6 |
| PMID | 18803808 |
| Title | Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders. |
| Abstract | Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-FOS expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 80 | Pharmacol. Biochem. Behav. 2008 Jan 88: 291-8 |
| PMID | 17920665 |
| Title | 5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine. |
| Abstract | 5-HT6 receptors have been implicated in consolidation of visuospatial and reward-based learning tasks. Since 5-HT6 receptors may be important in modulation of sensory gating which is often affected in schizophrenic patients, we tested whether Ro 4368554, a 5-HT6 selective antagonist at a dose of 10 mg/kg, could reverse the loss of prepulse inhibition from apomorphine or scopolamine. In addition, we also tested whether Ro 4368554 altered fear conditioning using fear potentiated startle, a model for emotional learning. Prepulse inhibition of startle was disrupted by apomorphine (0.5 mg/kg) when prepulse emissions were 5 dB above background but not above 15 dB, while scopolamine (0.5 mg/kg) caused disruption at both prepulse levels. Scopolamine-mediated disruption was not reversed by Ro 4368854 but apomorphine-mediated disruption was significantly ameliorated by 5-HT6 inhibition. For fear potentiated startle, scopolamine and/or Ro 4368554 were administered before two daily fear conditioning sessions; rats were tested on the following day. Rats that received scopolamine displayed no fear potentiated startle but Ro 4368554 reversed this scopolamine deficit. Additionally, we mapped FOS induction in rats treated with scopolamine and/or Ro 4368554; scopolamine increased FOS expression in the central nucleus of the amygdala and this was attenuated by Ro 4368554. In summary, we have demonstrated the efficacy of 5-HT6 antagonists in modulating sensory gating and fear conditioning, and thus may be of therapeutic use for schizophrenia-related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 81 | J Neural Transm (Vienna) 2009 Nov 116: 1529-41 |
| PMID | 19578925 |
| Title | Molecular mechanisms underlying synergistic effects of SSRI-antipsychotic augmentation in treatment of negative symptoms in schizophrenia. |
| Abstract | Negative symptoms in schizophrenia respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRIs). The molecular mechanisms underlying the augmentation are unclear. Nevertheless, significant progress has been made, pointing to some candidate systems which may be involved in SSRI-antipsychotic synergism. Thus, the enhanced dopamine release by SSRI-antipsychotic treatment is modulated by specific serotonergic receptors and by tyrosine hydroxylase. There are modifications in gamma-aminobutyric acid system via glutamate decarboxylase 67, protein kinase C beta and the receptor for activated C-kinase 1 (Rack1). Some studies indicate the input of transcription and neurotrophic factors as phospho-cyclic adenosine monophosphate response element-binding protein, FOS and fibroblast growth factor-2. Alterations in calcium signaling (neurogranin, regulator of G-protein signaling and Rack1) and in cytokine receptors for interleukin-8 and chemokine have also been reported. While as yet limited in scope, the evidence suggests definable molecular targets which may be implicated in drug development based on SSRI-antipsychotic synergistic actions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 82 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Mar 33: 290-5 |
| PMID | 19121361 |
| Title | Effects of acute and chronic administration of MK-801 on c-Fos protein expression in mice brain regions implicated in schizophrenia with or without clozapine. |
| Abstract | This study investigated the effects of acute and chronic administration of the non-competitive NMDA receptor antagonists MK-801 on c-FOS protein expression in different brain regions of mice with or without clozapine. MK-801 (0.6 mg/kg) acute administration produced a significant increase in the expression of c-FOS protein in the layers III-IV of posterior cingulate and retrosplenial (PC/RS) cortex, which was consistent with the previous reports. Moreover, we presented a new finding that MK-801 (0.6 mg/kg) chronic administration for 8 days produced a significant increase of c-FOS protein expression in the PC/RS cortex, prefrontal cortex (PFC) and hypothalamus of mice. Among that, c-FOS protein expression in the PC/RS cortex of mice was most significant. Compared to acute administration, we found that MK-801 chronic administration significantly increased the expression of c-FOS protein in the PC/RS cortex, PFC and hypothalamus. Furthermore, pretreatment of mice with clozapine significantly decreased the expression of c-FOS protein induced by MK-801 acute and chronic administration. These results suggest that c-FOS protein, the marker of neuronal activation, might play an important role in the chronic pathophysiological process of schizophrenic model induced by NMDA receptor antagonist. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 83 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Mar 33: 290-5 |
| PMID | 19121361 |
| Title | Effects of acute and chronic administration of MK-801 on c-Fos protein expression in mice brain regions implicated in schizophrenia with or without clozapine. |
| Abstract | This study investigated the effects of acute and chronic administration of the non-competitive NMDA receptor antagonists MK-801 on c-FOS protein expression in different brain regions of mice with or without clozapine. MK-801 (0.6 mg/kg) acute administration produced a significant increase in the expression of c-FOS protein in the layers III-IV of posterior cingulate and retrosplenial (PC/RS) cortex, which was consistent with the previous reports. Moreover, we presented a new finding that MK-801 (0.6 mg/kg) chronic administration for 8 days produced a significant increase of c-FOS protein expression in the PC/RS cortex, prefrontal cortex (PFC) and hypothalamus of mice. Among that, c-FOS protein expression in the PC/RS cortex of mice was most significant. Compared to acute administration, we found that MK-801 chronic administration significantly increased the expression of c-FOS protein in the PC/RS cortex, PFC and hypothalamus. Furthermore, pretreatment of mice with clozapine significantly decreased the expression of c-FOS protein induced by MK-801 acute and chronic administration. These results suggest that c-FOS protein, the marker of neuronal activation, might play an important role in the chronic pathophysiological process of schizophrenic model induced by NMDA receptor antagonist. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 84 | Front Behav Neurosci 2009 -1 3: 20 |
| PMID | 19750198 |
| Title | Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice. |
| Abstract | The alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) is expressed abundantly in the forebrain and is considered to have an essential role in synaptic plasticity and cognitive function. Previously, we reported that mice heterozygous for a null mutation of alpha-CaMKII (alpha-CaMKII+/-) have profoundly dysregulated behaviors including a severe working memory deficit, which is an endophenotype of schizophrenia and other psychiatric disorders. In addition, we found that almost all the neurons in the dentate gyrus (DG) of the mutant mice failed to mature at molecular, morphological and electrophysiological levels. In the present study, to identify the brain substrates of the working memory deficit in the mutant mice, we examined the expression of the immediate early genes (IEGs), c-FOS and Arc, in the brain after a working memory version of the eight-arm radial maze test. c-FOS expression was abolished almost completely in the DG and was reduced significantly in neurons in the CA1 and CA3 areas of the hippocampus, central amygdala, and medial prefrontal cortex (mPFC). However, c-FOS expression was intact in the entorhinal and visual cortices. Immunohistochemical studies using arc promoter driven dVenus transgenic mice demonstrated that arc gene activation after the working memory task occurred in mature, but not immature neurons in the DG of wild-type mice. These results suggest crucial insights for the neural circuits underlying spatial mnemonic processing during a working memory task and suggest the involvement of alpha-CaMKII in the proper maturation and integration of DG neurons into these circuits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 85 | Eur. J. Pharmacol. 2009 Oct 620: 27-35 |
| PMID | 19695244 |
| Title | F15063, a potential antipsychotic with dopamine D(2)/D(3) receptor antagonist and 5-HT(1A) receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum. |
| Abstract | Brain region-specific modulation of immediate-early gene (IEG) may constitute a marker of antipsychotic drug-like activity. We investigated the effects of the putative antipsychotic drug N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063), a compound that targets both dopamine D(2) and serotonin 5-HT(1A) receptors, in comparison with haloperidol and clozapine on rat mRNA expression of IEG i.e. the zinc-fingered transcription factors c-FOS, FOSB, zif268, c-jun and junB, two transcription factors of the nuclear receptor family nur77 and nor1, and the effector IEG arc. F15063 (10 mg/kg) and clozapine (10 mg/kg), but not haloperidol (0.63 mg/kg), induced c-FOS and FOSB mRNA expression in prefrontal cortex, a region associated with control of cognition and negative symptoms of schizophrenia. In striatum, only c-FOS, FOSB, junB and nur77 were induced by clozapine whereas all IEG mRNAs were increased by haloperidol and F15063 (from 2.5 mg/kg) with similar high efficacy despite a total absence of F15063-induced catalepsy. However, at 0.63 mg/kg, F15063 induced a lower degree of striatal IEG mRNA expression than haloperidol and pretreatment with the serotonin 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride (WAY100635) (0.63 mg/kg) increased the level of IEG mRNA induction by F15063. Furthermore, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] at 0.16 mg/kg decreased haloperidol-induced striatal IEG mRNA expression although it exerted no effects on its own. These results are consistent with an activation of serotonin 5-HT(1A) receptors by F15063, thus reducing D(2) blockade-induced striatal IEG mRNA. Furthermore, the substantial F15063-induced expression of IEGs such as c-FOS in striatum is not related to cataleptogenic activity and may act more as a marker of efficacious dopamine D(2) receptor blockade. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 86 | Pharmacol. Biochem. Behav. 2009 Nov 94: 16-23 |
| PMID | 19604496 |
| Title | D(1)/D(2) receptor-targeting L-stepholidine, an active ingredient of the Chinese herb Stephonia, induces non-rapid eye movement sleep in mice. |
| Abstract | L-stepholidine, an active ingredient of the Chinese herb Stephonia, is the first compound known to have mixed dopamine D(1) receptor agonist/D(2) antagonist properties and to be a potential treatment medication for schizophrenia. In schizophrenic patients insomnia is a common symptom and could be partly related to the presumed over-activity of the dopaminergic system. To elucidate whether stepholidine modulates sleep behaviors, we observed its effects on sleep-wake profiles in mice. The results showed that stepholidine administered i.p. at doses of 20, 40 or 80 mg/kg significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep, increased the amount of NREM sleep, and prolonged the duration of NREM sleep episodes, with a concomitant reduction in the amount of wakefulness. Stepholidine at doses of 40 and 80 mg/kg increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. However, stepholidine had no effect on either the amount of REM sleep or electroencephalogram power density of either NREM or REM sleep. Immunohistochemistry study showed that stepholidine dose-dependently increased c-FOS expression in neurons of the ventrolateral preoptic area, a sleep center in the anterior hypothalamus, as compared with the vehicle control. These results indicate that stepholidine initiates and maintains NREM sleep with activation of the sleep center in mice, suggesting its potential application for the treatment of insomnia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 87 | Neurobiol. Dis. 2009 Aug 35: 193-200 |
| PMID | 19379814 |
| Title | GSK3beta, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at serine-9. |
| Abstract | Accumulating evidence implicates deregulation of GSK3ss as a converging pathological event in Alzheimer's disease and in neuropsychiatric disorders, including bipolar disorder and schizophrenia. Although these neurological disorders share cognitive dysfunction as a hallmark, the role of GSK3ss in learning and memory remains to be explored in depth. We here report increased phosphorylation of GSK3ss at Serine-9 following cognitive training in two different hippocampus dependent cognitive tasks, i.e. inhibitory avoidance and novel object recognition task. Conversely, transgenic mice expressing the phosphorylation defective mutant GSK3ss[S9A] show impaired memory in these tasks. Furthermore, GSK3ss[S9A] mice displayed impaired hippocampal L-LTP and facilitated LTD. Application of actinomycin, but not anisomycin, mimicked GSK3ss[S9A] induced defects in L-LTP, suggesting that transcriptional activation is affected. This was further supported by decreased expression of the immediate early gene c-FOS, a target gene of CREB. The combined data demonstrate a role for GSK3ss in long term memory formation, by inhibitory phosphorylation at Serine-9. The findings are fundamentally important and relevant in the search for therapeutic strategies in neurological disorders associated with cognitive impairment and deregulated GSK3ss signaling, including AD, bipolar disorder and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 88 | Brain Res. 2009 Apr 1265: 186-95 |
| PMID | 19232330 |
| Title | Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress. |
| Abstract | Mice with reduced expression of the NR1 subunit of the NMDA receptor (NR1 hypomorphic mice) display altered behavioral phenotypes that may relate to behavioral characteristics of schizophrenia. Altered phenotypes in the NR1 hypomorphs include marked deficits in species-typical behavioral interactions in tests of social aggression and social affiliation. To gain insight into neuroanatomical circuits disrupted by reduced NMDA receptor function, the present work compared regional brain activation in NR1 hypomorphic mice and their wild type controls after a resident-intruder test. Induction of FOS protein was used as an index of neuronal activation. Wild type mice exhibited robust induction of FOS in select brain regions, including specific nuclei of the hypothalamus and amygdala, lateral septum, and widespread regions of the cerebral cortex. Although the behavioral patterns were different for male and female mice, neuroanatomical patterns of FOS induction were remarkably similar for the two sexes. To determine socially specific components of FOS induction by the resident-intruder test, responses were compared for mice assessed in a test of general arousal and stress involving forced swim. Some common brain regions were activated by both tests but regionally specific differences were also found. The NR1 hypomorphic mice tested in the resident-intruder procedure displayed distinctly different behavioral interactions compared to the wild type mice and exhibited a significantly blunted FOS response in almost all brain regions. The mutant mice also exhibited reduced FOS in response to swim stress in specific brain regions. These data suggest that the NR1 hypomorphic mice have functional activation deficits in response to social challenge and swim stress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 89 | Neuroscience 2009 Feb 158: 1215-23 |
| PMID | 19118604 |
| Title | Neurotensin inversely modulates maternal aggression. |
| Abstract | Neurotensin (NT) is a versatile neuropeptide involved in analgesia, hypothermia, and schizophrenia. Although NT is released from and acts upon brain regions involved in social behaviors, it has not been linked to a social behavior. We previously selected mice for high maternal aggression (maternal defense), an important social behavior that protects offspring, and found significantly lower NT expression in the CNS of highly protective females. Our current study directly tested NT's role in maternal defense. Intracerebroventricular (i.c.v.) injections of NT significantly impaired defense in terms of time aggressive and number of attacks at all doses tested (0.05, 0.1, 1.0, and 3.0 microg). Other maternal behaviors, including pup retrieval, were unaltered following NT injections (0.05 microg) relative to vehicle, suggesting specificity of NT action on defense. Further, i.c.v. injections of the NT receptor 1 (NT1) antagonist, SR 48692 (30 microg), significantly elevated maternal aggression in terms of time aggressive and attack number. To understand where NT may regulate aggression, we examined FOS following injection of either 0.1 microg NT or vehicle. Thirteen of 26 brain regions examined exhibited significant FOS increases with NT, including regions expressing NT1 and previously implicated in maternal aggression, such as lateral septum, bed nucleus of stria terminalis, paraventricular nucleus, and central amygdala. Together, our results indicate that NT inversely regulates maternal aggression and provide the first direct evidence that lowering of NT signaling can be a mechanism for maternal aggression. To our knowledge, this is the first study to directly link NT to a social behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 90 | Psychopharmacology (Berl.) 2009 Jan 202: 295-306 |
| PMID | 18925388 |
| Title | Asenapine restores cognitive flexibility in rats with medial prefrontal cortex lesions. |
| Abstract | Cognitive inflexibility in schizophrenia is treatment-resistant and predictive of poor outcome. This study examined the effect of asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, on cognitive dysfunction in the rat. The objective of this paper was to establish whether asenapine has a beneficial effect on the performance of rats with ibotenic acid-induced lesion of the medial prefrontal cortex (mPFC) in an intradimensional/extradimensional (ID/ED) test of cognitive flexibility. The effect of subcutaneously administered asenapine (0.75, 7.5, 75 microg/kg) on ID/ED performance of controls or mPFC-lesioned rats was examined using a within-subjects, repeated-measures design. In a second experiment, lesioned and control rats were tested with or without asenapine in a modified version of the task, with multiple set-shifts, before brains were processed for FOS-immunoreactivity in the mPFC. The mPFC lesion-induced deficit in the ID/ED task was stable with repeated testing over more than two months. Asenapine (75 microg/kg s.c., p < 0.05) completely restored the performance of lesioned rats. Experiment 2 replicated both lesion and asenapine effects and demonstrated that it is possible to measure set-shifting multiple times within a test session. Asenapine (75 microg/kg s.c.) was associated with differential activation of the neurons in the anterior mPFC of lesioned animals, but was without effect in controls. Asenapine can ameliorate mPFC lesion-induced impairment in attentional set-shifting, and is associated with a greater activation of the spared neurons in the anterior mPFC. These data suggest that asenapine may benefit impaired cognitive flexibility in disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 91 | Psychopharmacology (Berl.) 2009 Jan 201: 483-94 |
| PMID | 18762914 |
| Title | Preclinical investigations into the antipsychotic potential of the novel histamine H3 receptor antagonist GSK207040. |
| Abstract | To test the novel nonimidazole histamine H3 receptor antagonist 5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazapin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide (GSK207040) in a series of behavioral and neurochemical paradigms designed to evaluate its antipsychotic potential. Acute orally administered GSK207040 was investigated for its capacity to reverse a 24-h-induced deficit in novel object recognition memory, deficits in prepulse inhibition (PPI) induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. The acute neurochemical effects of GSK207040 were explored by analyzing rat anterior cingulate cortex microdialysates for levels of dopamine, noradrenaline, and acetylcholine and by c-FOS immunohistochemistry. The potential for interaction with the antipsychotic dopamine D2 receptor antagonist haloperidol was explored behaviorally (spontaneous locomotor activity and catalepsy), biochemically (plasma prolactin), and via ex vivo receptor occupancy determinations. GSK207040 significantly enhanced object recognition memory (3 mg/kg) and attenuated isolation rearing-induced deficits in PPI (1.0 and 3.2 mg/kg) but did not reverse amphetamine-induced increases in locomotor activity. There was no evidence of an interaction of GSK207040 with haloperidol. GSK207040 (3.2 mg/kg) raised extracellular concentrations of dopamine, noradrenaline, and acetylcholine in the anterior cingulate cortex and c-FOS expression in the core of the nucleus accumbens was increased at doses of 3.2 and 10.0 mg/kg. The behavioral and neurochemical profile of GSK207040 supports the potential of histamine H3 receptor antagonism to treat the cognitive and sensory gating deficits of schizophrenia. However, the failure of GSK207040 to reverse amphetamine-induced locomotor hyperactivity suggests that the therapeutic utility of histamine H(3) receptor antagonism versus positive symptoms is less likely, at least following acute administration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 92 | Pharmacol. Biochem. Behav. 2009 Nov 94: 16-23 |
| PMID | 19604496 |
| Title | D(1)/D(2) receptor-targeting L-stepholidine, an active ingredient of the Chinese herb Stephonia, induces non-rapid eye movement sleep in mice. |
| Abstract | L-stepholidine, an active ingredient of the Chinese herb Stephonia, is the first compound known to have mixed dopamine D(1) receptor agonist/D(2) antagonist properties and to be a potential treatment medication for schizophrenia. In schizophrenic patients insomnia is a common symptom and could be partly related to the presumed over-activity of the dopaminergic system. To elucidate whether stepholidine modulates sleep behaviors, we observed its effects on sleep-wake profiles in mice. The results showed that stepholidine administered i.p. at doses of 20, 40 or 80 mg/kg significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep, increased the amount of NREM sleep, and prolonged the duration of NREM sleep episodes, with a concomitant reduction in the amount of wakefulness. Stepholidine at doses of 40 and 80 mg/kg increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. However, stepholidine had no effect on either the amount of REM sleep or electroencephalogram power density of either NREM or REM sleep. Immunohistochemistry study showed that stepholidine dose-dependently increased c-FOS expression in neurons of the ventrolateral preoptic area, a sleep center in the anterior hypothalamus, as compared with the vehicle control. These results indicate that stepholidine initiates and maintains NREM sleep with activation of the sleep center in mice, suggesting its potential application for the treatment of insomnia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 93 | Neurosci. Lett. 2010 Jan 469: 127-30 |
| PMID | 19944746 |
| Title | The effects of glycine transporter I inhibitor, N-methylglycine (sarcosine), on ketamine-induced alterations in sensorimotor gating and regional brain c-Fos expression in rats. |
| Abstract | Reduced N-methyl-D-aspartate receptor (NMDAR) function may contribute to the pathogenesis of schizophrenia. Sarcosine, a potent glycine transporter inhibitor, can increase synaptic glycine and then promote NMDAR function. We assessed the antipsychotic potential of sarcosine by comparing the abilities of sarcosine and clozapine to restore the prepulse inhibition (PPI) deficit, hyperlocomotion and regional brain c-FOS expression changes caused by an NMDAR antagonist, ketamine. Four groups of rats were given acute injections, including saline+saline, saline+30 mg/kg ketamine, 100mg/kg sarcosine+30 mg/kg ketamine, and 15 mg/kg clozapine+30 mg/kg ketamine. Both sarcosine and clozapine reversed the ketamine-induced PPI deficit and hyperlocomotion. They both did not change ketamine-induced increase in c-FOS expression in the prefrontal cortex and nucleus accumbens. However, in the olfactory bulb, sarcosine, but not clozapine, significantly reduced the ketamine-induced increase in c-FOS expression. Our animal study demonstrated that sarcosine may have antipsychotic potential. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 94 | Brain Behav. Immun. 2010 Aug 24: 930-41 |
| PMID | 20227486 |
| Title | Maternal immune activation alters nonspatial information processing in the hippocampus of the adult offspring. |
| Abstract | The observation that maternal infection increases the risk for schizophrenia in the offspring suggests that the maternal immune system plays a key role in the etiology of schizophrenia. In a mouse model, maternal immune activation (MIA) by injection of poly(I:C) yields adult offspring that display abnormalities in a variety of behaviors relevant to schizophrenia. As abnormalities in the hippocampus are a consistent observation in schizophrenia patients, we examined synaptic properties in hippocampal slices prepared from the offspring of poly(I:C)- and saline-treated mothers. Compared to controls, CA1 pyramidal neurons from adult offspring of MIA mothers display reduced frequency and increased amplitude of miniature excitatory postsynaptic currents. In addition, the specific component of the temporoammonic pathway that mediates object-related information displays increased sensitivity to dopamine. To assess hippocampal network function in vivo, we used expression of the immediate-early gene, c-FOS, as a surrogate measure of neuronal activity. Compared to controls, the offspring of poly(I:C)-treated mothers display a distinct c-FOS expression pattern in area CA1 following novel object, but not novel location, exposure. Thus, the offspring of MIA mothers may have an abnormality in modality-specific information processing. Indeed, the MIA offspring display enhanced discrimination in a novel object recognition, but not in an object location, task. Thus, analysis of object and spatial information processing at both synaptic and behavioral levels reveals a largely selective abnormality in object information processing in this mouse model. Our results suggest that altered processing of object-related information may be part of the pathogenesis of schizophrenia-like cognitive behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 95 | Brain Res. 2010 Sep 1353: 152-8 |
| PMID | 20673759 |
| Title | Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the alpha(7) nicotinic acetylcholine receptor in Wistar rats. |
| Abstract | Nicotine has ameliorating effects on sensorimotor gating deficits in schizophrenia. We have shown that nicotine ameliorated disruption of prepulse inhibition (PPI) via the alpha(7) nicotinic acetylcholine receptor (nAChR) in Wistar rats. The 5-HT(3) receptor antagonist tropisetron was recently found to be an alpha(7) nAChR partial agonist. We initially investigated the effects of tropisetron on disruption of PPI induced by phencyclidine (PCP) (2mg/kg) or apomorphine (1mg/kg). Tropisetron had no effect on the disruption of PPI induced by PCP, but ameliorated the disruption by apomorphine. The ameliorating effect of tropisetron was antagonized by methyllycaconitine (2 or 5mg/kg), a partially selective alpha(7) nAChR antagonist. Next, to find the action site of tropisetron, we examined c-FOS protein expression in the nucleus accumbens (NAc), dorsolateral striatum (DLst) and ventral tegmental area (VTA). Tropisetron alone did not change the number of c-FOS-positive cells, whereas apomorphine increased the number of positive cells in the NAc and DLst. Tropisetron administration followed by apomorphine administration decreased the number of positive cells in the VTA compared with the apomorphine-alone group. These results suggest that tropisetron has an ameliorating effect on the sensorimotor gating deficits via the alpha(7) nAChR, and that one possible site of its action is the VTA. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 96 | Neuropharmacology 2010 Dec 59: 605-11 |
| PMID | 20732335 |
| Title | Selective deficits in spatial working memory in the neonatal ventral hippocampal lesion rat model of schizophrenia. |
| Abstract | The neonatal ventral hippocampal lesion (NVHL) manipulation is a neurodevelopmental animal model of schizophrenia that produces abnormalities in the prefrontal cortex and nucleus accumbens, both efferent targets of the hippocampus, and leads to spatial working memory impairments. To investigate the neuroanatomical basis of spatial working memory in NVHL animals, we assessed performance in two radial arm maze tasks known to be differentially sensitive to the two hippocampal efferent pathways, and measured levels of neuronal activation (FOS immunoreactivity [FOS-IR]) in the prefrontal cortex and nucleus accumbens following task performance. Neonatal rats (postnatal day 6-8) received excitotoxic lesions of the ventral hippocampus (n=25), or a sham procedure (infusions of artificial cerebrospinal fluid; n=22). Upon reaching adulthood, animals were trained in either a non-delayed random foraging task or a spatial delayed win-shift task. NVHL animals were impaired on the spatial delayed win-shift task, which depends on communication between hippocampus and prefrontal cortex, but were unimpaired on the non-delayed random foraging task, which requires connections between hippocampus and nucleus accumbens. FOS-IR in the nucleus accumbens was greater in NVHL animals than in shams following the random foraging task, despite similar levels of performance, while no group differences in FOS-IR in either the nucleus accumbens or prefrontal cortex were observed following win-shift performance. These results suggest that although the NVHL manipulation disrupts development of hippocampal efferents to both the prefrontal cortex and the nucleus accumbens, the disruption of hippocampal-prefrontal pathways has the dominant behavioral effect on spatial performance in NVHL rats. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 97 | Neuroscience 2010 Nov 170: 1153-64 |
| PMID | 20727386 |
| Title | Differences in responsiveness of mediodorsal thalamic and medial prefrontal cortical neurons to social interaction and systemically administered phencyclidine in rats. |
| Abstract | Phencyclidine (PCP) is a psychotomimetic drug that induces schizophrenia-like symptoms in healthy individuals and behavioral abnormalities with corresponding symptoms of schizophrenia in non-human animals. Our previous studies showed that systemically administered PCP produces tonic activation of neurons in the medial prefrontal cortex (mPFC) of rats and that this activation is mainly via excitatory inputs from regions outside the mPFC. Such long-lasting activation of PFC neurons is now considered to be a pivotal factor in PCP-induced behavioral abnormalities. Although our previous study identified the ventral hippocampus as a possible source of the excitatory inputs, it is not the only source innervating the mPFC. Several regions such as the thalamus also have monosynaptic projections to the mPFC. Recently, increased c-FOS expression by systemic PCP administration was reported in the mediodorsal nucleus of the thalamus (MD) and the centromedial nucleus of the thalamus (CM), which have strong reciprocal innervations with the mPFC. However, few studies have reported effects of PCP on the firing activity of MD/CM neurons in unanesthetized animals. In the current study in freely moving rats, we examined effects of systemically administered PCP on the spontaneous firing activity of the MD/CM, after identifying the response properties of recorded neurons in social interaction with an unfamiliar partner. About 30% of MD/CM neurons recorded exhibited tonic excitation following systemic PCP administration, whereas only a few neurons (7%) were inhibited by PCP. The proportion of MD neurons activated by systemic PCP administration was about half of that in the mPFC. Although the proportion of neurons responsive to social interaction did not differ between the two regions (40%), neurons activated during social interaction in the mPFC (90%) were more likely to be affected by systemic PCP administration than those in the MD/CM (45%). These results suggest that neurons responsive to social interaction in the mPFC may be differently affected by PCP than those in the MD/CM. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 98 | Genes Brain Behav. 2010 Oct 9: 703-11 |
| PMID | 20546314 |
| Title | Strain-specific proportion of the two isoforms of the dopamine D2 receptor in the mouse striatum: associated neural and behavioral phenotypes. |
| Abstract | Genetic variability in the proportion of the two alternative dopamine D2 receptor (D2R) mRNA splice variants, D2R-long (D2L) and D2R-short (D2S), influence corticostriatal functioning and could be implicated in liability to psychopathology. This study compared mesostriatal D2L/D2S ratios and associated neural and behavioral phenotypes in mice of the DBA/2J and C57BL/6J-inbred strains, which differ for schizophrenia- and addiction-like phenotypes. Results showed that DBA/2J mice lack the striatal predominance of D2L that has been reported in the rat and in C57BL/6J mice and confirmed in the latter strain by this study. Only C57BL/6J mice showed enhanced striatal c-FOS expression under D1R and D2/3R co-stimulation, indicating synergistic interaction between the subtypes of DA receptors. Instead, DBA/2J mice were characterized by opposing effects of D2/3R and D1R stimulation on striatal c-FOS expression, in line with a more pronounced influence of D2S isoform, and did not express stereotyped climbing under D1R and D2/3R co-stimulation, as reported for D2L-/- mice. Finally, strain-specific modulation of c-FOS expression by D1R and D2/3R co-stimulation was selectively observed in striatal compartments receiving inputs from the prefrontal cortex and involved in the control of motivated behaviors. These results show differences in tissue-specific D2R splicing in mice with intact genotypes and support a role for this phenotype in individual variability of corticostriatal functioning and in liability to psychopathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 99 | J. Neurochem. 2010 Aug 114: 1205-16 |
| PMID | 20533993 |
| Title | Repeated administration of alpha7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases alpha7 nAChR levels in the brain. |
| Abstract | The alpha7 nicotinic acetylcholine receptor (nAChR) is an important target for treatment of cognitive deficits in schizophrenia and Alzheimer's disease. However, the receptor desensitizes rapidly in vitro, which has led to concern regarding its applicability as a clinically relevant drug target. Here we investigate the effects of repeated agonism on alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 nAChR binding sites in several brain regions, particularly in the prefrontal cortex. The alpha7 nAChR agonists SSR180711 and PNU-282987 also increase [(125)I]-BTX binding, suggesting that this is a general consequence of alpha7 nAChR agonism. Interestingly, the alpha7 nAChR positive allosteric modulators PNU-120596 and NS1738 do not increase [(125)I]-BTX binding. Furthermore, A-582941-induced increase in Arc and c-FOS mRNA expression in the prefrontal cortex is enhanced and unaltered, respectively, after repeated administration, demonstrating that the alpha7 nAChRs remain responsive. Contrarily, A-582941-induced phosphorylation of Erk2 in the prefrontal cortex occurs following acute, but not repeated administration. Our results demonstrate that repeated agonist administration increases the number of alpha7 nAChRs in the brain, and leads to coupling versus uncoupling of specific intracellular signaling pathways. Additionally, our data suggest a fundamental difference between the sequelae of repeated administration with agonists and allosteric modulators of the alpha7 nAChR. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 100 | Neuroscience 2010 Aug 169: 158-70 |
| PMID | 20447448 |
| Title | Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia. |
| Abstract | Serotonin2C (5-HT(2C)) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and schizophrenia. Whether abnormal movements initiated by 5-HT(2C) receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT(2C) agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-FOS in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT(2C) antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced FOS expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced FOS expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of FOS labeling. Ro-60-0175 (1-3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT(2C) agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete modifications in associative territories. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 101 | Physiol Res 2010 -1 59: 811-9 |
| PMID | 20406041 |
| Title | Pain perception in neurodevelopmental animal models of schizophrenia. |
| Abstract | Animal models are important for the investigation of mechanisms and therapeutic approaches in various human diseases, including schizophrenia. Recently, two neurodevelopmental rat models of this psychosis were developed based upon the use of subunit selective N-methyl-D-aspartate receptor agonists--quinolinic acid (QUIN) and N-acetyl-aspartyl-glutamate (NAAG). The aim of this study was to evaluate pain perception in these models. QUIN or NAAG was infused into lateral cerebral ventricles neonatally. In the adulthood, the pain perception was examined. The rats with neonatal brain lesions did not show any significant differences in acute mechanical nociception and in formalin test compared to controls. However, the neonatally lesioned rats exhibited significantly higher pain thresholds in thermal nociception. Increased levels of mechanical hyperalgesia, accompanying the sciatic nerve constriction (neuropathic pain), were also observed in lesioned rats. Although hyperalgesia was more pronounced in QUIN-treated animals, the number of c-FOS-immunoreactive neurons of the lumbar spinal cord was similar in experimental and control rats. We conclude that neonatal brain lesions attenuated the thermal perception in both nociceptive and neuropathic pain whereas mechanical pain was increased in the model of neuropathic pain only. Thus, nociceptive and neuropathic pain belongs--in addition to behavioral changes--among the parameters which are affected in described animal models of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 102 | Neuroscience 2010 Jul 168: 787-96 |
| PMID | 20399255 |
| Title | Effect of CFMTI, an allosteric metabotropic glutamate receptor 1 antagonist with antipsychotic activity, on Fos expression in regions of the brain related to schizophrenia. |
| Abstract | The main purpose of this study was to explore the sites and mechanisms of action of metabotropic glutamate receptor 1 (mGluR1) blockade for antipsychotic-like activity using a FOS mapping approach, with the intent of better understanding the similarities and differences between the pharmacological actions of mGluR1 antagonists and atypical antipsychotic drugs such as clozapine. Previously, we showed that an allosteric mGluR1 antagonist (negative allosteric modulator), 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one (CFMTI), induces FOS expression in the nucleus accumbens and the medial prefrontal cortex (mPFC), but not in the dorsolateral striatum, similar to the action of clozapine. In the present study, the FOS expression profile of CFMTI was more extensively evaluated in various areas of the brain. CFMTI induced FOS expression mainly in glutamatergic neurons in the mPFC, in a manner similar to clozapine. A significant increase in FOS expression was also observed in the locous coeruleus, central amygdaloid nucleus, the bed nucleus of the stria terminalis and the primary somatosensory cortex, but not in the ventral tegmental area, dorsal raphe or lateral septum. FOS expression in orexin neurons in the lateral hypothalamic/perifornical area (LH/PFA) is known to be positively correlated with the weight gain liability of atypical antipsychotics. CFMTI did not increase FOS expression in orexin neurons in the LH/PFA, in contrast to clozapine, which does have weight gain liability. These results suggest that CFMTI has unique and shared actions on FOS expression in various regions of the brain compared with clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 103 | Neuroscience 2010 Jun 168: 498-504 |
| PMID | 20338222 |
| Title | Projections from ventral hippocampus to medial prefrontal cortex but not nucleus accumbens remain functional after fornix lesions in rats. |
| Abstract | Sensorimotor gating, as measured by prepulse inhibition (PPI) of startle, is deficient in human beings with schizophrenia and is greatly reduced in rats after bilateral infusion of N-methyl-D-aspartate (NMDA) into the ventral hippocampus (VH). The disruption of PPI by bilateral VH NMDA infusion is blocked by bilateral medial prefrontal cortex (mPFC) lesions, but not by bilateral lesions of the fornix, which is the principal output pathway of the hippocampal formation of the VH. Tract-tracing studies have shown the presence of additional nonfornical pathways by which the VH and neighboring structures of the amygdala may reach forebrain regions that regulate PPI, including the mPFC. To determine whether these nonfornical pathways might mediate forebrain activation after VH NMDA infusion, we examined the effects of bilateral VH NMDA infusion on c-FOS protein expression in the mPFC and nucleus accumbens (NAC) after sham vs. bilateral fornix lesions. Significant increases of c-FOS expression were observed in both the mPFC and NAC after bilateral VH NMDA infusions. Fornix lesions blocked enhanced c-FOS expression in the NAC but not the mPFC after VH NMDA infusion. The results suggest that an intact fornix may be necessary for VH activation of the NAC, but that the VH uses additional nonfornical projections to activate PPI-regulatory circuits within the mPFC. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 104 | Cereb. Cortex 2010 Sep 20: 2092-102 |
| PMID | 20051354 |
| Title | Distinct neural pathways mediate ?7 nicotinic acetylcholine receptor-dependent activation of the forebrain. |
| Abstract | alpha(7) nicotinic acetylcholine receptor (nAChR) agonists are candidates for the treatment of cognitive deficits in schizophrenia. Selective alpha(7) nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (ACCshell) in rats, regions important for cognitive function. However, the neural substrates involved in these effects remain elusive. Here we identify cortically projecting cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain (BF) as important targets for alpha(7) nAChR activation, as measured by c-FOS immunoreactivity, a marker of neuronal activation. Selective depletion of these cholinergic neurons abolishes the SSR180711-induced activation of the mPFC but not the ACCshell, demonstrating their critical importance for alpha(7) nAChR-dependent activation of the mPFC. Contrarily, selective depletion of dopaminergic neurons in the ventral tegmental area abolishes the SSR180711-induced activation of the ACCshell but not the mPFC or HDB. These results demonstrate 2 distinct neural pathways activated by SSR180711. The BF and mPFC are important for attentional function and may subserve the procognitive effects of alpha(7) nAChR agonists, whereas activation of the ACCshell is implicated in the beneficial effect of antipsychotics on the positive symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 105 | Pharmacol. Res. 2010 May 61: 430-6 |
| PMID | 20045056 |
| Title | Antipsychotic-like effects of the N-methyl-D-aspartate receptor modulator neboglamine: an immunohistochemical and behavioural study in the rat. |
| Abstract | Neboglamine is a functional modulator of the glycine site on the N-methyl-d-aspartate (NMDA) receptor. Dysfunction of this receptor has been associated with negative and cognitive symptoms in schizophrenia. Thus, we tested the hypothesis that neboglamine behaves as a potential antipsychotic. We compared the effects of neboglamine, D-serine, clozapine, and haloperidol on the expression of FOS-like immunoreactivity (FLI), a marker of neuronal activation, in rat forebrain. We also studied the effects of these agents on phencyclidine (PCP)-induced behaviour in rats, a model predictive of potential antipsychotic activity. Neboglamine, like haloperidol and clozapine, significantly increased the number of FLI-positive cells in the prefrontal cortex, nucleus accumbens, and lateral septal nucleus (3.2-, 4.8-, and 4.5-fold over control, respectively). Haloperidol dramatically increased FLI (390-fold over control) in the dorsolateral striatum, a brain region in which neboglamine and clozapine had no effect. The pattern of FLI induced by neboglamine closely matched that of d-serine, an endogenous agonist at the glycine site of NMDA receptors. Consistent with this finding, neboglamine restored NMDA-mediated neurotransmitter release in frontal cortex punches exposed to the NMDA antagonist PCP. In the behavioural model, all test compounds significantly inhibited PCP-induced hyperlocomotion. Unlike haloperidol and clozapine, neither neboglamine nor D-serine affected the basal levels of locomotor activity. Moreover, oral neboglamine dose-dependently inhibited both the hyperlocomotion and the frequency of rearing behaviour induced by PCP. These results, while confirming that the NMDA glycine site is a feasible target for activating the frontostriatal system, support the clinical evaluation of neboglamine as a treatment for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 106 | Biol. Psychiatry 2010 Apr 67: 788-92 |
| PMID | 19880093 |
| Title | Cortical-striatal integration of cocaine history and prefrontal dysfunction in animal modeling of dual diagnosis. |
| Abstract | High rates of substance disorders in schizophrenia and other mental illnesses may reflect biological vulnerabilities to the addiction process. Interactions between addictive drug effects and mental illness involving circuits that generate motivated behavior may underpin this vulnerability. We examined separate and combined effects of neonatal ventral hippocampal lesions (NVHLs)-a neurodevelopmental model of schizophrenia (vs. SHAM-operated control animals)--and a behaviorally sensitizing cocaine history (15 mg/kg/day x 5 days vs. saline injections) on acute cocaine-induced neural activation signaled by c-FOS expression. Stereological assessment of activation densities spanned six ventral to dorsal cortical-striatal compartments. Cortically, NVHLs showed hypoactivation and decreased volume of the ventral medial prefrontal cortex. In contrast, cocaine history was only expressed subcortically and as a hyperactivating effect in the dorsal striatum where significant NVHL-induced hyperactivation also emerged. Across all subjects and brain regions, only dorsal striatal activation was correlated with differences in sensitized locomotion. However, this activation was tightly correlated to a simple multiplicative function of ventral medial prefrontal hypoactivation and cocaine history-related increases in striatal activation. These findings suggest drug history and developmental temporal limbic abnormalities associated with prefrontal dysfunction produce compounding effects within cortical-striatal circuits as mechanistic basis for dual diagnosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 107 | Brain Res. 2010 Jan 1307: 166-76 |
| PMID | 19840778 |
| Title | Increased sensitivity to kainic acid in a genetic model of reduced NMDA receptor function. |
| Abstract | The pathophysiology of schizophrenia may involve reduced NMDA receptor function and experimental models of NMDA receptor hypofunction have proven useful for characterizing neurobiological abnormalities potentially relevant to schizophrenia. The present study assessed behavioral responses and induction of FOS after administration of kainic acid to wild type mice (NR1(+/+)) and mice with genetically reduced NMDA receptor expression (NR1(neo/neo)). At a dose of 20 mg/kg, kainic acid induced lethal seizures in 100% of the NR1(neo/neo) mice tested but produced no lethal seizures in the wild type mice. The NR1(neo/neo) mice also exhibited enhanced behavioral responses to kainic acid at a dose of 15 mg/kg but no lethal seizures were produced by this dose. A greater induction of FOS was observed in neocortical and limbic cortical regions of the NR1(neo/neo) compared to NR1(+/+) mice after administration of 15 mg/kg kainic acid. In contrast, there were no differences between the genotypes in kainic acid induced FOS in the amygdala, hippocampus, lateral septum, and nucleus accumbens. In order to determine if altered behavioral phenotypes of the NR1(neo/neo) mice could be related to increased sensitivity of kainate receptors to endogenous glutamate, effects of the highly selective kainate antagonist LY382884 were examined. The kainate antagonist reduced the exaggerated acoustic startle responses, deficits in prepulse inhibition of acoustic startle, and motor hyperactivity in the NR1(neo/neo) mice. These findings suggest that selective kainate receptor antagonists could be novel therapeutic candidates for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 108 | Int. J. Neuropsychopharmacol. 2010 Feb 13: 109-22 |
| PMID | 19531280 |
| Title | Prefrontal cortex and reversion of atropine-induced disruption of the degraded contingency effect by antipsychotic agents and N-desmethylclozapine in rats. |
| Abstract | Interactive context processing is a cognitive ability that is altered in psychotic states, including schizophrenia. This deficit has been linked to prefrontal cortical dysfunction in humans. The degraded contingency effect (DCE) is a simple form of interactive context processing by which contextual information interferes with a target conditioned stimulus for control over conditioned responding. We have previously shown that the DCE was disrupted by the muscarinic receptor antagonist atropine and that this disruption was specifically restored by cholinergic drugs displaying an antipsychotic-like profile, such as physostigmine or xanomeline. The DCE was selectively associated with an increase in FOS immunoreactivity in the medial prefrontal cortex (mPFC), an increase that was not observed in the presence of atropine. Here, we set out to test the actions of typical, atypical and potential antipsychotics on atropine-induced disruption of the DCE and the related mPFC FOS-immunoreactivity profile. Low doses of haloperidol, olanzapine, clozapine and N-desmethylclozapine reversed atropine-induced disruption of the DCE, but with different dose-dependent curves (linear shapes for haloperidol and N-desmethylclozapine, inverted U shapes for olanzapine and clozapine). The level of FOS within the mPFC paralleled the pharmacological profile of the different drugs. Compared to contingent control groups, an increased level of FOS immunoreactivity within the mPFC was observed only with doses that reversed atropine-induced disruption of the DCE. These results suggest that the deficit of interactive context processing, which is a hallmark of psychotic states, might originate from a mere deficit of fundamental associative processes. This deficit might result from a cholinergic blockade of the PFC. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 109 | Psychopharmacology (Berl.) 2010 Sep 212: 105-15 |
| PMID | 20623106 |
| Title | The effects of clozapine on quinpirole-induced non-regulatory drinking and prepulse inhibition disruption in rats. |
| Abstract | The biological underpinnings of schizophrenic polydipsia are poorly understood. This study is aimed at fulfilling the requisites of an experimental model of this syndrome through the quinpirole (QNP) induction of non-regulatory drinking in rats. In a first experiment, clozapine (10 and 40 mg/kg p.o.) was substituted for haloperidol during the last 5 days of 10 days QNP (0.5 mg/kg i.p.) administration and water intake measured at 5 h. In a second experiment, animals treated with QNP alone or in combination with clozapine were assessed for water intake and prepulse inhibition (PPI). Expression of genes coding for the dopaminergic D2 receptor, as well as for the early genes BDNF (brain-derived neurotrophic factor) and c-FOS in prefrontal cortex, hippocampus, and striatum was also evaluated. Clozapine prevented QNP-induced drinking at 10 and 40 mg/kg, but only at 40 mg/kg when it was substituted for haloperidol. In the second experiment, QNP-treated rats showed both non-regulatory drinking and PPI disruption. Both these effects were prevented by clozapine 40 mg/kg. QNP-reduced BDNF expression in the hippocampus and increased c-FOS in the prefrontal cortex. This effect was prevented by clozapine. Given by itself, clozapine reduced the expression of both D2 receptors and BDNF in the prefrontal cortex and striatum. The present study lends further support to the hypothesis that non-regulatory drinking induced by QNP in rats is a robust and reliable pharmacological effect that might model psychotic polydipsia also in its sensitivity to clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 110 | Transl Psychiatry 2011 -1 1: e9 |
| PMID | 22832404 |
| Title | Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms. |
| Abstract | Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug--yohimbine, and an anti-anxiety drug--diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders--notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 111 | Mol. Cell. Neurosci. 2011 Aug 47: 293-305 |
| PMID | 21635953 |
| Title | Evidence for altered hippocampal function in a mouse model of the human 22q11.2 microdeletion. |
| Abstract | 22q11.2 chromosomal deletions are recurrent copy number mutations that increase the risk of schizophrenia around thirty-fold. Deletion of the orthologous chromosomal region in mice offers an opportunity to characterize changes to neuronal structure and function that may account for the development of this disease. The hippocampus has been implicated in schizophrenia pathogenesis, is reduced in volume in 22q11.2 deletion carriers and displays altered neuronal structure in a mouse model of the mutation (Df(16)A(+/-) mice). Here we investigate hippocampal CA1 physiology, hippocampal-dependent spatial memory and novelty-induced hippocampal activation in Df(16)A(+/-) mice. We found normal spatial reference memory (as assayed by the Morris water maze test) as well as modest but potentially important deficits in physiology. In particular, a reduction in the level of inhibition of CA1 pyramidal neurons was observed, implying a decrease in interneuron activity. Additionally, deficits in LTP were observed using certain induction protocols. Induction of c-FOS expression by exploration of a novel environment suggested a relative sparing of CA1 and dentate gyrus function but showed a robust decrease in the number of activated CA3 pyramidal neurons in Df(16)A(+/-) mice. Overall, experiments performed in this 22q11.2 deletion model demonstrated deficits of various degrees across different regions of the hippocampus, which together may contribute to the increased risk of developing schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 112 | Clin Psychopharmacol Neurosci 2011 Apr 9: 36-43 |
| PMID | 23431025 |
| Title | Effects of Aripiprazole and Haloperidol on Fos-like Immunoreactivity in the Prefrontal Cortex and Amygdala. |
| Abstract | Aripiprazole, a dopamine system stabilizer, shows efficacy against both negative symptoms and positive symptoms in patients with schizophrenia. The aim of this study was to investigate the effects of aripiprazole and haloperidol on c-FOS expression in rat brain. Aripiprazole (1, 10 and 30 mg/kg, i.p.) and haloperidol (0.1 and 1 mg/kg, i.p.) were administered to adult Male Sprague-Dawley rats. After 2 h of drug or vehicle administration, the rats were killed and their brains were removed and perfused with fixative, then cut into 40 µm slices on a freezing microtome. Brain regions of interest were the medial prefrontal cortex (mPFC), the nucleus accumbens core and shell (NAC-C and NAC-S), the hippocampus (CA1, CA3 and DG), the central amygdala (Ce), the basolateral amygdala (BL) and the temporal cortex (Tc). Immunohistochemistry was performed to label cell bodies containing c-FOS. The administration of aripiprazole at all doses (1, 10 or 30 mg/kg) resulted in greater FOS-like immunoreactivity (FLI) in the investigated brain areas, as compared to the vehicle. Comparable increases in FLI were demonstrated in the NAC-C and NAC-S in response to both aripiprazole and haloperidol treatment. The administration of haloperidol (0.1 or 1 mg/kg) also resulted in greater FLI in the investigated brain areas, except the mPFC, where no changes were observed. In the Ce and BL, a significant increase in FOS-positive neurons was observed only with 0.1 mg/kg of haloperidol. Both aripiprazole and haloperidol increased FLI in limbic areas, which are considered important targets of antipsychotic drugs. The differential action of aripiprazole on FLI in the amygdala and mPFC as compared to haloperidol may be a good way to differentiate atypical from typical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 113 | Transl Psychiatry 2011 -1 1: e33 |
| PMID | 22832607 |
| Title | Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo. |
| Abstract | Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains. Disruption of the CAV1 gene has recently been identified as a rare structural variant associated with schizophrenia. Although Cav-1 knockout (KO) mice displayed no baseline behavioral disruptions, Cav-1 KO mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1. Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5-HT(2A)-selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI. We also discovered that genetic deletion of Cav-1 attenuated 5-HT(2A)-induced c-FOS and egr-1 expression in mouse frontal cortex and also reduced 5-HT(2A)-mediated Ca(2+) mobilization in primary cortical neuronal cultures. The behavioral effects of the 5-HT(2A) agonist (2,5-dimethoxy-4-iodoamphetamine) including head twitch responses and disruption of PPI were also attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (that is, atypical antipsychotic drug) and agonist actions at 5-HT(2A) receptors. This study demonstrates that disruption of the CAV1 gene--a rare structural variant associated with schizophrenia--is not only pro-psychotic but also attenuates atypical antipsychotic drug actions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 114 | Physiol. Behav. 2011 Oct 104: 796-803 |
| PMID | 21843541 |
| Title | Fos expression following regimens of predator stress versus footshock that differentially affect prepulse inhibition in rats. |
| Abstract | Stress is suggested to exacerbate symptoms and contribute to relapse in patients with schizophrenia and several other psychiatric disorders. A prominent feature of many of these illnesses is an impaired ability to filter information through sensorimotor gating processes. Prepulse inhibition (PPI) is a functional measure of sensorimotor gating, and known to be deficient in schizophrenia and sometimes in post-traumatic stress disorder (PTSD), both of which are also sensitive to stress-induced symptom deterioration. We previously found that a psychological stressor (exposure to a ferret without physical contact), but not footshock, disrupted PPI in rats, suggesting that intense psychological stress/trauma may uniquely model stress-induced sensorimotor gating abnormalities. In the present experiment, we sought to recreate the conditions where we found this behavioral difference, and to explore possible underlying neural substrates. Rats were exposed acutely to ferret stress, footshock, or no stress (control). 90 min later, tissue was obtained for FOS immunohistochemistry to assess neuronal activation. Several brain regions (prelimbic, infralimbic, and cingulate cortices, the paraventricular hypothalamic nucleus, the paraventricular thalamic nucleus, and the lateral periaqueductal gray) were equally activated following exposure to either stressor. Interestingly, the medial amygdala and dorsomedial periaqueductal gray had nearly twice as much FOS activation in the ferret-exposed rats as in the footshock-exposed rats, suggesting that higher activation within these structures may contribute to the unique behavioral effects induced by predator stress. These results may have implications for understanding the neural substrates that could participate in sensorimotor gating abnormalities seen in several psychiatric disorders after psychogenic stress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 115 | Neuropsychopharmacology 2011 Jul 36: 1703-13 |
| PMID | 21490590 |
| Title | Schizophrenia-like attentional deficits following blockade of prefrontal cortex GABAA receptors. |
| Abstract | Attentional deficits are a core symptom of schizophrenia. Post-mortem analyses of the brains of schizophrenics reveal consistent abnormalities in ?-aminobutyric acid (GABA) interneurons indicative of reduced cortical GABA transmission, raising the possibility that this pathology contributes to attentional deficits. We examined whether blockade of prefrontal cortex (PFC) GABA(A) receptors with bicuculline (BMI) impairs attention in rats using the 5-choice serial reaction time task (5CSRTT). For comparison, we also examined whether administration of the GABA(A) receptor agonist muscimol (MUS) would improve attention. In parallel, we examined the effects of both manipulations on activity in an open field and on motivation using the intracranial self-stimulation (ICSS) test. BMI increased PFC neuronal activity, as reflected by increased FOS immunolabeling, and impaired attention, as reflected by decreased accuracy and increased omissions. Although increased omissions also may reflect reductions in locomotor activity or motivation, the overall pattern of effects does not support either of these interpretations: BMI did not affect locomotor activity, and it enhanced motivation in the ICSS test. MUS did not affect attention, although it increased impulsive behavior at a dose that suppressed PFC neuronal activity, as reflected by decreased FOS immunolabeling. These impulsivity effects are not due to altered locomotor activity (which was decreased) or motivation (which was not affected). Our data support the hypothesis that cortical GABA neurons have an important role in regulating attention and may have direct implications for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 116 | Neuropsychopharmacology 2011 May 36: 1248-59 |
| PMID | 21326191 |
| Title | Continuous, but not intermittent, antipsychotic drug delivery intensifies the pursuit of reward cues. |
| Abstract | Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-FOS and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine-mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 117 | J. Neurosci. 2011 Feb 31: 1863-72 |
| PMID | 21289196 |
| Title | Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT?A and mGlu? receptors in the adult offspring. |
| Abstract | Epidemiological studies indicate that maternal influenza viral infection increases the risk for schizophrenia in the adult offspring. The serotonin and glutamate systems are suspected in the etiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. The effects of hallucinogens, such as psilocybin and mescaline, require the serotonin 5-HT(2A) receptor, and induce schizophrenia-like psychosis in humans. In addition, metabotropic glutamate receptor mGlu(2/3) agonists show promise as a new treatment for schizophrenia. Here, we investigated the level of expression and behavioral function of 5-HT(2A) and mGlu(2) receptors in a mouse model of maternal influenza viral infection. We show that spontaneous locomotor activity is diminished by maternal infection with the mouse-adapted influenza A/WSN/33 (H1N1) virus. The behavioral responses to hallucinogens and glutamate antipsychotics are both affected by maternal exposure to influenza virus, with increased head-twitch response to hallucinogens and diminished antipsychotic-like effect of the glutamate agonist. In frontal cortex of mice born to influenza virus-infected mothers, the 5-HT(2A) receptor is upregulated and the mGlu(2) receptor is downregulated, an alteration that may be involved in the behavioral changes observed. Additionally, we find that the cortical 5-HT(2A) receptor-dependent signaling pathways are significantly altered in the offspring of infected mothers, showing higher c-FOS, egr-1, and egr-2 expression in response to the hallucinogenic drug DOI. Identifying a biochemical alteration that parallels the behavioral changes observed in a mouse model of prenatal viral infection may facilitate targeting therapies for treatment and prevention of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 118 | Biol. Psychiatry 2011 May 69: 918-27 |
| PMID | 21251645 |
| Title | Activation of thalamocortical networks by the N-methyl-D-aspartate receptor antagonist phencyclidine: reversal by clozapine. |
| Abstract | Noncompetitive N-methyl-D-aspartate receptor antagonists are widely used as pharmacological models of schizophrenia. Their neurobiological actions are still poorly understood, although the prefrontal cortex (PFC) appears as a key target area. We examined the effect of phencyclidine (PCP) on neuronal activity of the mediodorsal (MD) and centromedial (CM) thalamic nuclei, reciprocally connected with the PFC, using extracellular recordings (n = 50 neurons from 35 Wistar rats) and c-FOS expression. Phencyclidine (.25 mg/kg intravenous [IV]) markedly disorganized the activity of MD/CM neurons, increasing (424%) and decreasing (41%) the activity of 57% and 20% of the recorded neurons, respectively (23% remained unaffected). Phencyclidine reduced delta oscillations (.15-4 Hz) as assessed by recording local field potentials. The subsequent clozapine administration (1 mg/kg IV) reversed PCP effects on neuronal discharge and delta oscillations. Double in situ hybridization experiments revealed that PCP (10 mg/kg intraperitoneal [IP]) markedly increased c-FOS expression in glutamatergic neurons of several cortical areas (prefrontal, somatosensory, retrosplenial, entorhinal) and in thalamic nuclei, including MD/CM. Phencyclidine also increased c-FOS expression in the amygdala; yet, it had a small effect in the hippocampus. Phencyclidine did not increase c-FOS expression in gamma-aminobutyric acidergic cells except in hippocampus, amygdala, somatosensory, and retrosplenial cortices. Clozapine (5 mg/kg IP) had no effect by itself but significantly prevented PCP-induced c-FOS expression. Phencyclidine likely exerts its psychotomimetic action by increasing excitatory neurotransmission in thalamo-cortico-thalamic networks involving, among others, PFC, retrosplenial, and somatosensory cortices. The antipsychotic action of clozapine includes, among other actions, an attenuation of the neuronal hyperactivity in thalamocortical networks. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 119 | Int. J. Neuropsychopharmacol. 2011 Oct 14: 1165-78 |
| PMID | 21087552 |
| Title | Partial agonists in schizophrenia--why some work and others do not: insights from preclinical animal models. |
| Abstract | While dopamine D2 receptor partial agonists (PAs) have been long considered for treating schizophrenia, only one, aripiprazole, is clinically available for therapeutic use. This raises critically important questions as to what is unique about aripiprazole and to what extent animal models can predict therapeutic success. A number of PAs whose clinical fate is known: aripiprazole, preclamol, terguride, OPC-4392 and bifeprunox were compared to haloperidol (a reference antipsychotic) in several convergent preclinical animal models; i.e. amphetamine-induced locomotion (AIL) and conditioned avoidance response (CAR), predictive of antipsychotic effects; unilateral nigrostriatal lesioned rats, a model of hypo-dopaminergia; striatal FOS induction, a molecular marker for antipsychotic activity; and side-effects common to this class of drugs: catalepsy (motor side-effects) and prolactaemia. The results were compared across drugs with reference to their measured striatal D2 receptor occupancy. All the PAs occupied striatal D2 receptors in a dose dependent manner, inhibited AIL and CAR, and lacked motor side-effects or prolactinaemia despite D2 receptor occupancy exceeding 80%. At comparative doses, aripiprazole distinguished itself from the other PAs by causing the least rotation in the hypo-dopaminergic model (indicating the least intrinsic activity) and showed the highest FOS expression in the nucleus accumbens (indicating functional D2 antagonism). Although a number of PAs are active in antipsychotic animal models, not all of them succeed. Given that only aripiprazole is clinically available, it can be inferred that low functional intrinsic activity coupled with sufficient functional antagonism as reflected in the animal models may be a marker of success. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 120 | Eur. J. Neurosci. 2011 Jan 33: 161-74 |
| PMID | 21073553 |
| Title | Excessive novelty-induced c-Fos expression and altered neurogenesis in the hippocampus of GluA1 knockout mice. |
| Abstract | ?-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit-deficient (GluA1-/-) mice display novelty-induced hyperactivity, cognitive and social defects and may model psychiatric disorders, such as schizophrenia and depression/mania. We used c-FOS expression in GluA1-/- mice to identify brain regions responsible for novelty-induced hyperlocomotion. Exposure to a novel cage for 2 h significantly increased c-FOS expression in many brain regions in both wild-type and knockout mice. Interestingly, the clearest genotype effect was observed in the hippocampus and its main input region, the entorhinal cortex, where the novelty-induced c-FOS expression was more strongly enhanced in GluA1-/- mice. Their novelty-induced hyperlocomotion partly depended on the activity of AMPA receptors, as it was diminished by the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide (NBQX) and unaffected by the AMPA receptor potentiator 2,3-dihydro-1,4-benzodioxin-6-yl-1-piperidinylmethanone (CX546). The hyperlocomotion of GluA1-/- mice was normalised to the level of wild-type mice within 5-6 h, after which their locomotion followed normal circadian rhythm and was not affected by acute or chronic treatments with the selective serotonin reuptake inhibitor escitalopram. We propose that hippocampal dysfunction, as evidenced by the excessive c-FOS response to novelty, is the major contributor to novelty-induced hyperlocomotion in GluA1-/- mice. Hippocampal dysfunction was also indicated by changes in proliferation and survival of adult-born dentate gyrus cells in the knockout mice. These results suggest focusing on the functions of hippocampal formation, such as novelty detection, when using the GluA1-/- mouse line as a model for neuropsychiatric and cognitive disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 121 | Int. J. Neuropsychopharmacol. 2011 Feb 14: 17-28 |
| PMID | 20196921 |
| Title | Cannabinoid CB1 receptor antagonism prevents neurochemical and behavioural deficits induced by chronic phencyclidine. |
| Abstract | Clinical and laboratory studies suggest that the endocannabinoid system is involved in schizophrenia disorders. Recent evidence indicates that cannabinoid receptor (CB1) antagonists have a pharmacological profile similar to antipsychotic drugs. We investigated the behavioural and biochemical effects of the CB1 antagonist AM251 in a phencyclidine (PCP) animal paradigm modelling the cognitive deficit and some negative symptoms of schizophrenia. Chronic AM251 (0.5 mg/kg for 3 wk) improved the PCP-altered recognition memory, as indicated by a significant amelioration of the discrimination index compared to chronic PCP alone (2.58 mg/kg for 1 month). AM251 also reversed the PCP-induced increase in immobility in the forced swim test resembling avolition, a negative sign of schizophrenia. In order to analyse the mechanisms underlying these behaviours, we studied the effects of AM251 on the endocannabinoid system (in terms of CB1 receptor density and functional activity and endocannabinoid levels) and c-FOS protein expression. The antagonist counteracted the alterations in CB1 receptor function induced by PCP in selected cerebral regions involved in schizophrenia. In addition, in the prefrontal cortex, the key region in the integration of cognitive and negative functions, AM251 markedly raised anandamide levels and reversed the PCP-induced increase of 2-arachidonoylglycerol concentrations. Finally, chronic AM251 fully reversed the PCP-elicited expression of c-FOS protein in the prefrontal cortical region. These findings suggest an antipsychotic-like profile of the CB1 cannabinoid receptor antagonist which, by restoring the function of the endocannabinoid system, might directly or indirectly normalize some of the neurochemical maladaptations present in this schizophrenia-like animal model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 122 | Transl Psychiatry 2011 -1 1: e33 |
| PMID | 22832607 |
| Title | Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo. |
| Abstract | Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains. Disruption of the CAV1 gene has recently been identified as a rare structural variant associated with schizophrenia. Although Cav-1 knockout (KO) mice displayed no baseline behavioral disruptions, Cav-1 KO mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1. Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5-HT(2A)-selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI. We also discovered that genetic deletion of Cav-1 attenuated 5-HT(2A)-induced c-FOS and egr-1 expression in mouse frontal cortex and also reduced 5-HT(2A)-mediated Ca(2+) mobilization in primary cortical neuronal cultures. The behavioral effects of the 5-HT(2A) agonist (2,5-dimethoxy-4-iodoamphetamine) including head twitch responses and disruption of PPI were also attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (that is, atypical antipsychotic drug) and agonist actions at 5-HT(2A) receptors. This study demonstrates that disruption of the CAV1 gene--a rare structural variant associated with schizophrenia--is not only pro-psychotic but also attenuates atypical antipsychotic drug actions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 123 | Neuropsychopharmacology 2011 Jul 36: 1703-13 |
| PMID | 21490590 |
| Title | Schizophrenia-like attentional deficits following blockade of prefrontal cortex GABAA receptors. |
| Abstract | Attentional deficits are a core symptom of schizophrenia. Post-mortem analyses of the brains of schizophrenics reveal consistent abnormalities in ?-aminobutyric acid (GABA) interneurons indicative of reduced cortical GABA transmission, raising the possibility that this pathology contributes to attentional deficits. We examined whether blockade of prefrontal cortex (PFC) GABA(A) receptors with bicuculline (BMI) impairs attention in rats using the 5-choice serial reaction time task (5CSRTT). For comparison, we also examined whether administration of the GABA(A) receptor agonist muscimol (MUS) would improve attention. In parallel, we examined the effects of both manipulations on activity in an open field and on motivation using the intracranial self-stimulation (ICSS) test. BMI increased PFC neuronal activity, as reflected by increased FOS immunolabeling, and impaired attention, as reflected by decreased accuracy and increased omissions. Although increased omissions also may reflect reductions in locomotor activity or motivation, the overall pattern of effects does not support either of these interpretations: BMI did not affect locomotor activity, and it enhanced motivation in the ICSS test. MUS did not affect attention, although it increased impulsive behavior at a dose that suppressed PFC neuronal activity, as reflected by decreased FOS immunolabeling. These impulsivity effects are not due to altered locomotor activity (which was decreased) or motivation (which was not affected). Our data support the hypothesis that cortical GABA neurons have an important role in regulating attention and may have direct implications for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 124 | Neuroscience 2012 Aug 216: 38-45 |
| PMID | 22561731 |
| Title | Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons. |
| Abstract | The cortical cholinergic innervation, which is important for memory and cognition, has been implicated in schizophrenia. To experimentally analyze such a possible role of the cholinergic system, we have used the dissociative drug phencyclidine (PCP), known to produce schizophrenia-like psychosis in humans, to model aspects of schizophrenia in rats. We previously showed that induced cortical cholinergic hypofunction leads to enhanced PCP-induced locomotor activity and attenuated social interaction. After PCP, rats lacking cortical cholinergic innervation also show impaired declarative memory. To directly study the role of the basalo-cortical cholinergic projections for PCP-induced neural activation in different cortical areas, we have now monitored the rapid (30 and 60 min) effects of low doses of PCP (2 and 3mg/kg) on neural activation as reflected by transcriptional activation of c-FOS in cortical areas, using quantitative in situ hybridization. We find an almost pan-cortical neural induction of c-FOS mRNA with doses of PCP low enough not to alter levels of either BDNF or Nogo receptor mRNA levels. Specific unilateral lesioning of the uncrossed cholinergic projections to the cortical mantle by 192-IgG-saporin immunotoxin delivery to nc basalis (NBM) caused a striking ipsilateral decrease of the PCP-induced cortical c-FOS mRNA induction, restricted to areas which had become effectively denervated. Because PCP at low doses is unlikely to directly influence cortical neurons, we suggest that it acts by activation of the cholinergic input, which in turn leads to cortical c-FOS mRNA increases. Our results are compatible with a role for the cholinergic system in symptoms of schizophrenia, by showing that the basalo-cortical cholinergic projections are needed in order for PCP to have full activating effects on cortical neurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 125 | Acta Neurobiol Exp (Wars) 2012 -1 72: 207-18 |
| PMID | 23093008 |
| Title | Local blockade of NMDA receptors in the rat prefrontal cortex increases c-Fos expression in multiple subcortical regions. |
| Abstract | Ketamine, phencyclidine and MK801 are uncompetitive NMDA receptor (NMDAR) antagonists which are used widely to model certain features of schizophrenia in rats. Systemic administration of NMDAR antagonists, in addition to provoking an increase in c-FOS expression, leads to important neurochemical and electrophysiological changes within the medial prefrontal cortex (mPFC). Since the mPFC is considered to exert a top-down regulatory control of subcortical brain regions, we examined the effects of local infusion of the NMDAR antagonist, MK801, into the mPFC on the expression of c-FOS protein (widely used marker of neuronal activation) in several subcortical structures. The experiment was performed on freely moving rats, bilaterally implanted with guide cannulae in the prelimbic mPFC, infused with MK801 or saline. Bilateral administration of MK801 to the mPFC produced changes in the behavior (increased stereotypy and decreased sleep-like behavior) and complex changes in c-FOS protein expression with significant increases observed in the nucleus accumbens (core and shell), amygdala (basolateral and central nuclei), the CA1 field of the hippocampus, and mediodorsal and paraventricular thalamic nuclei, as compared to the saline group. Together, we demonstrate that blockade of NMDA receptors in the mPFC is sufficient to lead to behavioral abnormalities and increased c-FOS expression in many, but not all, of the subcortical structures examined. Our findings suggest that some of the behavioral abnormalities produced by uncompetitive NMDAR antagonists may result from aberrant activity in cortico-subcortical pathways. These data support an increasing body of literature, suggesting that the mPFC is an important site mediating the effects of NMDAR antagonists. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 126 | PLoS ONE 2012 -1 7: e46604 |
| PMID | 23029555 |
| Title | Npas4: a neuronal transcription factor with a key role in social and cognitive functions relevant to developmental disorders. |
| Abstract | Npas4 is a transcription factor, which is highly expressed in the brain and regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity. A deregulation of the inhibitory-excitatory balance has been associated with a variety of human developmental disorders such as schizophrenia and autism. However, not much is known about the role played by inhibitory synapses and inhibitory pathways in the development of nervous system disorders. We hypothesized that alterations in the inhibitory pathways induced by the absence of Npas4 play a major role in the expression of the symptoms observed in psychiatric disorders. To test this hypothesis we tested mice lacking the transcription factor (Npas4 knock-out mice (Npas4-KO)) in a battery of behavioral assays focusing on general activity, social behaviors, and cognitive functions. Npas4-KO mice are hyperactive in a novel environment, spend less time exploring an unfamiliar ovariectomized female, spend more time avoiding an unfamiliar male during a first encounter, show higher social dominance than their WT littermates, and display pre-pulse inhibition, working memory, long-term memory, and cognitive flexibility deficits. These behavioral deficits may replicate schizophrenia-related symptomatology such as social anxiety, hyperactivity, and cognitive and sensorimotor gating deficits. Immunohistochemistry analyses revealed that Npas4 expression is induced in the hippocampus after a social encounter and that Npas4 regulates the expression of c-FOS in the CA1 and CA3 regions of the hippocampus after a cognitive task. Our results suggest that Npas4 may play a major role in the regulation of cognitive and social functions in the brain with possible implications for developmental disorders such as schizophrenia and autism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 127 | Neuropharmacology 2012 Mar 62: 1413-21 |
| PMID | 21110986 |
| Title | T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats. |
| Abstract | T-type calcium channels are important in burst firing and expressed in brain regions implicated in schizophrenia. Therefore, we examined the effects of novel selective T-type calcium channel antagonists in preclinical assays predictive of antipsychotic-like activity. TTA-A2 blocked the psychostimulant effects of amphetamine and MK-801 and decreased conditioned avoidance responding. These effects appeared mechanism based, rather than compound specific, as two structurally dissimilar T-type antagonists also reduced amphetamine-induced psychomotor activity. Importantly, the ability to reduce amphetamine's effects was maintained following 20 days pre-treatment with TTA-A2. To explore the neural substrates mediating the observed behavioral effects, we examined the influence of TTA-A2 on amphetamine-induced c-FOS expression as well as basal and stimulant-evoked dopamine and glutamate release in the nucleus accumbens. TTA-A2 decreased amphetamine-induced c-FOS expression as well as MK-801-induced, but not basal, glutamate levels in the nucleus accumbens. Basal, amphetamine- and MK-801-induced dopamine efflux was altered. These findings suggest that T-type calcium channel antagonism could represent a novel mechanism for treating schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 128 | Pharmacol. Biochem. Behav. 2012 Dec 103: 174-80 |
| PMID | 22960130 |
| Title | Neuroanatomical substrates of the disruptive effect of olanzapine on rat maternal behavior as revealed by c-Fos immunoreactivity. |
| Abstract | Olanzapine is one of the most widely prescribed atypical antipsychotic drugs in the treatment of schizophrenia. Besides its well-known side effect on weight gain, it may also impair human parental behavior. In this study, we took a preclinical approach to examine the behavioral effects of olanzapine on rat maternal behavior and investigated the associated neural basis using the c-FOS immunohistochemistry. On postpartum days 6-8, Sprague-Dawley mother rats were given a single injection of sterile water or olanzapine (1.0, 3.0 or 5.0mg/kg, sc). Maternal behavior was tested 2h later, after which rats were sacrificed and brain tissues were collected. Ten brain regions that were either implicated in the action of antipsychotic drugs and/or in the regulation of maternal behavior were examined for c-FOS immunoreactivity. Acute olanzapine treatment dose-dependently disrupted various components of maternal behavior (e.g., pup retrieval, pup licking, nest building, crouching) and increased c-FOS immunoreactivity in the medial prefrontal cortex (mPFC), nucleus accumbens shell and core (NAs and NAc), dorsolateral striatum (DLSt), ventral lateral septum (LSv), central amygdala (CeA) and ventral tegmental area (VTA), important brain areas generally implicated in the incentive motivation and reward processing. In contrast, olanzapine treatment did not alter c-FOS in the medial preoptic nucleus (MPN), ventral bed nucleus of the stria terminalis (vBST) and medial amygdala (MeA), the core brain areas directly involved in the mediation of rat maternal behavior. These findings suggest that olanzapine disrupts rat maternal behavior primarily by suppressing incentive motivation and reward processing via its action on the mesocorticolimbic dopamine systems, other limbic and striatal areas, but not by disrupting the core processes involved in the mediation of maternal behavior in particular. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 129 | Neuropsychopharmacology 2012 Oct 37: 2522-30 |
| PMID | 22781838 |
| Title | Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice. |
| Abstract | Prepulse inhibition (PPI) deficits are among the most reproducible phenotypic markers found in schizophrenic patients. We recently reported that nisoxetine, a selective norepinephrine transporter (NET) inhibitor, reversed the PPI deficits that have been identified in dopamine transporter (DAT) knockout (KO) mice. However, the mechanisms underlying nisoxetine-induced PPI recovery in DAT KO mice were unclear in previous experiments. To clarify these mechanisms, PPI was tested after microinjections of nisoxetine into the medial prefrontal cortex (mPFc) or nucleus accumbens (NAc) in wildtype (WT) and DAT KO mice. c-FOS immunohistochemistry provided an indicator of neural activation. Multiple-fluorescent-labeling procedures and the retrograde tracer fluorogold were employed to identify nisoxetine-activated neurons and circuits. Systemic nisoxetine activated the mPFc, the NAc shell, the basolateral amygdala, and the subiculum. Infusions of nisoxetine into the mPFc reversed PPI deficits in DAT KO mice, but produced no changes in WT mice, while infusion of nisoxetine into the NAc had no effect on PPI in both WT and DAT KO mice. Experiments using multiple-fluorescent labeling/fluorogold revealed that nisoxetine activates presumed glutamatergic pyramidal cells that project from the mPFc to the NAc. Activated glutamatergic projections from the mPFc to the NAc appear to have substantial roles in the ability of a NET inhibitor to normalize PPI deficits in DAT KO. Thus, this data suggest that selective NET inhibitors such as nisoxetine might improve information processing deficits in schizophrenia via regulation of cortico-subcortical neuromodulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 130 | Synapse 2012 Oct 66: 885-92 |
| PMID | 22733588 |
| Title | Differential role of serotonin projections from the dorsal and median raphe nuclei in phencyclidine-induced hyperlocomotion and fos-like immunoreactivity in rats. |
| Abstract | Altered brain serotonin activity is implicated in schizophrenia. We have previously shown differential involvement of serotonergic projections from the dorsal or median raphe nucleus in phencyclidine-induced hyperlocomotion in rats, a behavioral model of aspects of schizophrenia. Here we further investigated the effects of serotonergic lesions of the raphe nuclei on phencyclidine-induced hyperlocomotion by parallel assessment of FOS-like immunoreactivity (FLI), a marker of neuronal activation in the brain. Male Sprague-Dawley rats were anesthetized with pentobarbitone and stereotaxically microinjected with 5 ?g of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into either the dorsal raphe (DRN) or median raphe nucleus (MRN). Two weeks after the surgery, rats with lesions of the MRN, but not those with lesions of the DRN, showed significant enhancement of the hyperlocomotion induced by injection of 2.5 mg/kg of phencyclidine. Rats with MRN lesions also showed significantly higher levels of FLI in the polymorphic layer of the dentate gyrus in the dorsal hippocampus (PoDG) when compared with sham-operated controls. Rats with lesions of the DRN showed significantly higher levels of FLI in the nucleus accumbens (NAcc). These results indicate that FLI in the PoDG, but not the NAcc, correlates with enhanced phencyclidine-induced locomotor hyperactivity in MRN-lesioned rats. These results support our previous studies suggesting a role of serotonergic projections from the MRN to the dorsal hippocampus in some of the symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 131 | PLoS ONE 2012 -1 7: e37820 |
| PMID | 22693577 |
| Title | Individual variations in maternal care early in life correlate with later life decision-making and c-fos expression in prefrontal subregions of rats. |
| Abstract | Early life adversity affects hypothalamus-pituitary-adrenal axis activity, alters cognitive functioning and in humans is thought to increase the vulnerability to psychopathology--e.g. depression, anxiety and schizophrenia--later in life. Here we investigated whether subtle natural variations among individual rat pups in the amount of maternal care received, i.e. differences in the amount of licking and grooming (LG), correlate with anxiety and prefrontal cortex-dependent behavior in young adulthood. Therefore, we examined the correlation between LG received during the first postnatal week and later behavior in the elevated plus maze and in decision-making processes using a rodent version of the Iowa Gambling Task (rIGT). In our cohort of male and female animals a high degree of LG correlated with less anxiety in the elevated plus maze and more advantageous choices during the last 10 trials of the rIGT. In tissue collected 2 hrs after completion of the task, the correlation between LG and c-FOS expression (a marker of neuronal activity) was established in structures important for IGT performance. Negative correlations existed between rIGT performance and c-FOS expression in the lateral orbitofrontal cortex, prelimbic cortex, infralimbic cortex and insular cortex. The insular cortex correlations between c-FOS expression and decision-making performance depended on LG background; this was also true for the lateral orbitofrontal cortex in female rats. Dendritic complexity of insular or infralimbic pyramidal neurons did not or weakly correlate with LG background. We conclude that natural variations in maternal care received by pups may significantly contribute to later-life decision-making and activity of underlying brain structures. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 132 | Schizophr. Res. 2012 Apr 136: 88-95 |
| PMID | 22104138 |
| Title | The role of endogenous neurotensin in psychostimulant-induced disruption of prepulse inhibition and locomotion. |
| Abstract | The neuropeptide neurotensin (NT) is closely associated with dopaminergic and glutamatergic systems in the rat brain. Central injection of NT into the nucleus accumbens (NAcc) or peripheral administration of NT receptor agonists, reduces many of the behavioral effects of psychostimulants. However, the role of endogenous NT in the behavioral effects of psychostimulants (e.g. DA agonists and NMDA receptor antagonists) remains unclear. Using a NTR antagonist, SR142948A, the current studies were designed to examine the role of endogenous NT in DA receptor agonist- and NMDA receptor antagonist-induced disruption of prepulse inhibition of the acoustic startle response (PPI), locomotor hyperactivity and brain-region specific c-FOS mRNA expression. Adult male rats received a single i.p. injection of SR142948A or vehicle followed by D-amphetamine, apomorphine or dizocilpine challenge. SR142948A had no effect on baseline PPI, but dose-dependently attenuated d-amphetamine- and dizocilpine-induced PPI disruption and enhanced apomorphine-induced PPI disruption. SR142948A did not significantly affect either baseline locomotor activity or stimulant-induced hyperlocomotion. Systemic SR142948A administration prevented c-FOS mRNA induction in mesolimbic terminal fields (prefrontal cortex, lateral septum, NAcc, ventral subiculum) induced by all three psychostimulants implicating the VTA as the site for NT modulation of stimulant-induced PPI disruption. Further characterization of the NT system may be valuable to find clinical useful compounds for schizophrenia and drug addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 133 | Cereb. Cortex 2012 Jul 22: 1487-97 |
| PMID | 21893679 |
| Title | 5-HT1A receptor agonists enhance pyramidal cell firing in prefrontal cortex through a preferential action on GABA interneurons. |
| Abstract | 5-HT(1A) receptors (5-HT1AR) are expressed by pyramidal and ?-aminobutyric acidergic (GABAergic) neurons in medial prefrontal cortex (mPFC). Endogenous serotonin inhibits mPFC pyramidal neurons via 5-HT1AR while 5-HT1AR agonists, given systemically, paradoxically excite ventral tegmental area-projecting pyramidal neurons. This enhances mesocortical dopamine function, a process involved in the superior efficacy of atypical antipsychotic drugs on negative and cognitive symptoms of schizophrenia. Moreover, the 5-HT1AR-induced increase of pyramidal discharge may also contribute to the maintenance of activity patterns required for working memory, impaired in schizophrenia. Given the importance of these processes, we examined the neurobiological basis of pyramidal activation through 5-HT1AR using the prototypical agent 8-OH-DPAT. (±)8-OH-DPAT (7.5 ?g/kg i.v.) increased discharge rate and c-FOS expression in rat mPFC pyramidal neurons. Local blockade of GABA(A) inputs with gabazine (SR-95531) avoided (±)8-OH-DPAT-induced excitations of pyramidal neurons. Moreover, (±)8-OH-DPAT administration reduced the discharge rate of mPFC fast-spiking GABAergic interneurons at doses exciting pyramidal neurons. Activation of other 5-HT1AR subpopulations (raphe nuclei or hippocampus) does not appear to contribute to pyramidal excitations. Overall, the present data suggest a preferential action of (±)8-OH-DPAT on 5-HT1AR in GABAergic interneurons. This results in pyramidal disinhibition and subsequent downstream excitations of subcortical structures reciprocally connected with PFC, such as midbrain dopaminergic neurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 134 | Int. J. Neuropsychopharmacol. 2012 Mar 15: 267-80 |
| PMID | 20923599 |
| Title | Long-lasting recovery of psychotic-like symptoms in isolation-reared rats after chronic but not acute treatment with the cannabinoid antagonist AM251. |
| Abstract | In this work we investigated the ability of AM251 to reverse schizophrenia-like symptoms produced by a neurodevelopmental animal model based on a social isolation procedure. First, we assessed the validity of our isolation-rearing protocol and, as expected, isolation-reared rats showed hyperlocomotion in a novel environment, cognitive impairment in the novel object recognition (NOR) test and a significant increase in the number of aggressive behaviours in the social interaction test compared to group-housed controls. This behavioural picture was associated with a reduction in CB? receptor/G protein coupling in specific brain areas as well as reduced c-FOS immunoreactivity in the prefrontal cortex and caudate putamen. In this model, chronic but not acute treatment with the CB? receptor antagonist AM251 counteracted isolation-induced cognitive impairment in the NOR test and aggressive behaviours in the social interaction test. This behavioural recovery was accompanied by the rescue of CB? receptor functionality and c-FOS levels in all brain regions altered in isolation-reared rats. Moreover, chronic AM251 also increased c-FOS immunoreactivity in the nucleus accumbens, as previously demonstrated for antipsychotic drugs. Interestingly, the behavioural recovery due to chronic AM251 administration persisted until 10 d after discontinuing the treatment, indicating a long-lasting effect of the cannabinoid antagonist on psychotic-like symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 135 | Neuropsychopharmacology 2012 Oct 37: 2522-30 |
| PMID | 22781838 |
| Title | Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice. |
| Abstract | Prepulse inhibition (PPI) deficits are among the most reproducible phenotypic markers found in schizophrenic patients. We recently reported that nisoxetine, a selective norepinephrine transporter (NET) inhibitor, reversed the PPI deficits that have been identified in dopamine transporter (DAT) knockout (KO) mice. However, the mechanisms underlying nisoxetine-induced PPI recovery in DAT KO mice were unclear in previous experiments. To clarify these mechanisms, PPI was tested after microinjections of nisoxetine into the medial prefrontal cortex (mPFc) or nucleus accumbens (NAc) in wildtype (WT) and DAT KO mice. c-FOS immunohistochemistry provided an indicator of neural activation. Multiple-fluorescent-labeling procedures and the retrograde tracer fluorogold were employed to identify nisoxetine-activated neurons and circuits. Systemic nisoxetine activated the mPFc, the NAc shell, the basolateral amygdala, and the subiculum. Infusions of nisoxetine into the mPFc reversed PPI deficits in DAT KO mice, but produced no changes in WT mice, while infusion of nisoxetine into the NAc had no effect on PPI in both WT and DAT KO mice. Experiments using multiple-fluorescent labeling/fluorogold revealed that nisoxetine activates presumed glutamatergic pyramidal cells that project from the mPFc to the NAc. Activated glutamatergic projections from the mPFc to the NAc appear to have substantial roles in the ability of a NET inhibitor to normalize PPI deficits in DAT KO. Thus, this data suggest that selective NET inhibitors such as nisoxetine might improve information processing deficits in schizophrenia via regulation of cortico-subcortical neuromodulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 136 | Schizophr Bull 2013 May 39: 692-702 |
| PMID | 22927669 |
| Title | Prior haloperidol, but not olanzapine, exposure augments the pursuit of reward cues: implications for substance abuse in schizophrenia. |
| Abstract | Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain's dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-FOS mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 137 | Neuropsychobiology 2013 -1 68: 139-45 |
| PMID | 24051542 |
| Title | Facial affect recognition performance and event-related potentials in violent and non-violent schizophrenia patients. |
| Abstract | We investigated whether male inpatients with schizophrenia and a history of hands-on violent offences (forensic schizophrenic, FOS) are more impaired in emotion recognition than matched schizophrenia patients without any history of violence (general psychiatric schizophrenic, GPS). This should become apparent in performance in psychometry and in scalp event-related brain potentials (ERPs) evoked by pictures of facial affect. FOS and GPS (each n = 19) were matched concerning age, intelligence, comorbid addiction, medication and illness duration. FOS revealed significantly poorer affect recognition (AR) performance, especially of neutral and fear stimuli. Analysis of ERPs revealed a significant interaction of hemisphere, electrode position and group of the N250 component. Post hoc analysis of group effect showed significantly larger amplitudes in FOS at FC3. These results support the hypothesis that in FOS emotional faces are more salient and evoke higher arousal. Larger impairment in AR performance combined with higher salience and arousal may contribute to the occurrence of violent acts in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 138 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 1-12 |
| PMID | 23800465 |
| Title | Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis. |
| Abstract | Administration of NMDA receptor antagonists, such as ketamine and MK-801, may induce psychotic-like behaviors in preclinical models of schizophrenia. Ketamine has also been observed to exacerbate psychotic symptoms in schizophrenia patients. However, memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease and proposed for antipsychotic augmentation, may challenge this view. To date, the molecular mechanisms by which these NMDA receptor antagonists cause different neurochemical, behavioral, and clinical effects are still a matter of debate. Here, we investigated by molecular imaging whether these agents could differently modulate gene expression and topographical distribution of glutamatergic postsynaptic density (PSD) proteins. We focused on Homer1a/Homer1b/PSD-95 signaling network, which may be implicated in glutamate-dependent synaptic plasticity, as well as in psychosis pathophysiology and treatment. Ketamine (25 and 50mg/kg) and MK-801 (0.8mg/kg) significantly induced the transcripts of immediate-early genes (Arc, c-FOS, and Homer1a) in cortical regions compared to vehicle, whereas they reduced Homer1b and PSD-95 expression in cortical and striatal regions. Differently, memantine (5mg/kg) did not increase Homer1a signal compared to vehicle, whereas it induced c-FOS in the somatosensory and in the medial agranular cortices. Moreover, memantine did not affect Homer1b and PSD-95 expression. When compared to ketamine and MK-801, memantine significantly increased the expression of c-FOS, Homer1b and PSD-95. Overall, ketamine and MK-801 prominently increased Homer1a/Homer1b expression ratio, whereas memantine elicited the opposite effect. These data may support the view that ketamine, MK-801 and memantine exert divergent effects on PSD transcripts, which may contribute to their partially different behavioral and clinical effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 139 | J. Chem. Neuroanat. 2013 Sep 52: 20-4 |
| PMID | 23660497 |
| Title | Deep brain stimulation of the mediodorsal thalamic nucleus yields increases in the expression of zif-268 but not c-fos in the frontal cortex. |
| Abstract | This study explores the regions activated by deep brain stimulation of the mediodorsal thalamic nucleus through examination of immediate early genes as markers of neuronal activation. Stimulation was delivered unilaterally with constant current 100 ?s duration pulses at a frequency of 130 Hz delivered at an amplitude of 200 ?A for 3h. Brains were removed, sectioned and radio-labelled for the IEGs zif-268 and c-FOS. In anaesthetised rats, deep brain stimulation of mediodorsal thalamic nucleus produced robust increases in the expression of zif-268 but not c-FOS localised to regions that are reciprocally connected with the mediodorsal thalamic nucleus, including the prelimbic and orbitofrontal cortices, and the premotor cortex indicating an increase in synaptic activity in these regions. These findings map those brain regions that are persistently, rather than transiently, activated by high frequency electrical stimulation of the mediodorsal thalamic nucleus by a putatively antidromic mechanism which may be relevant to neuropsychiatric disorders such as schizophrenia in which thalamocortical systems are disrupted and in which DBS protocols are being considered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 140 | Neuroscience 2013 Oct 250: 189-200 |
| PMID | 23867766 |
| Title | Reversal of novelty-induced hyperlocomotion and hippocampal c-Fos expression in GluA1 knockout male mice by the mGluR2/3 agonist LY354740. |
| Abstract | Dysfunctional glutamatergic neurotransmission has been implicated in schizophrenia and mood disorders. As a putative model for these disorders, a mouse line lacking the GluA1 subunit (GluA1-KO) of the ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor displays a robust novelty-induced hyperlocomotion associated with excessive neuronal activation in the hippocampus. Agonists of metabotropic glutamate 2/3 receptors (mGluR2/3) inhibit glutamate release in various brain regions and they have been shown to inhibit neuronal activation in the hippocampus. Here, we tested a hypothesis that novelty-induced hyperlocomotion in the GluA1-KO mice is mediated via excessive hippocampal neuronal activation by analyzing whether an mGluR2/3 agonist inhibits this phenotypic feature. GluA1-KO mice and littermate wildtype (WT) controls were administered with (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) (15 mg/kg, i.p.) 30 min before a 2-h exposure to novel arenas after which c-FOS immunopositive cells were analyzed in the hippocampus. LY354740 (15 mg/kg) decreased hyperactivity in male GluA1-KO mice, with only a minimal effect in WT controls. This was observed in two cohorts of animals, one naïve to handling and injections, another pre-handled and accustomed to injections. LY354740 (15 mg/kg) also reduced the excessive c-FOS expression in the dorsal hippocampal CA1 pyramidal cell layer in maleGluA1-KO mice, while not affecting c-FOS levels in WT mice. In female mice, no significant effect for LY354740 (15 mg/kg) on hyperactive behavior or hippocampal c-FOS was observed in either genotype or treatment cohort. A higher dose of LY354740 (30 mg/kg) alleviated hyperlocomotion of GluA1-KO males, but not that of GluA1-KO females. In conclusion, the excessive behavioral hyperactivity of GluA1-KO mice can be partly prevented by reducing neuronal excitability in the hippocampus with the mGluR2/3 agonist suggesting that the hippocampal reactivity is strongly involved in the behavioral phenotype of GluA1-KO mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 141 | Behav. Brain Res. 2013 Apr 242: 178-90 |
| PMID | 23291154 |
| Title | Chronic administration of risperidone in a rat model of schizophrenia: a behavioural, morphological and molecular study. |
| Abstract | In the present work we analyzed the effect of the chronic administration of risperidone (2mg/kg over 65 days) on behavioural, morphological and molecular aspects in an experimental model of schizophrenia obtained by bilateral injection of ibotenic acid into the ventral hippocampus of new-born rats. Our results show that during their adult lives the animals with hippocampal lesions exhibit different alterations, mainly at behavioural level and in the gene expression of dopamine D(2) and 5-HT(2A) receptors. However, at morphological level the study performed on the prefrontal cortex did not reveal any alterations in either the thickness or the number of cells immunoreactive for c-FOS, GFAP, CBP or PV. Overall, risperidone administration elicited a trend towards the recovery of the values previously altered by the hippocampal lesion, approaching the values seen in the animals without lesions. It may be concluded that the administration of risperidone in the schizophrenia model employed helps to improve the altered functions, with no significant negative effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 142 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Jan 40: 353-63 |
| PMID | 23142770 |
| Title | Clozapine regulation of p90RSK and c-Fos signaling via the ErbB1-ERK pathway is distinct from olanzapine and haloperidol in mouse cortex and striatum. |
| Abstract | Treatment of the positive psychotic symptoms of schizophrenia with standard antipsychotic drugs (APDs) is ineffective in a proportion of cases. For these treatment resistant patients the alternative is the APD clozapine which is superior to other agents but carries serious side effects. Why clozapine is uniquely effective is unknown, but we have previously postulated may involve G-protein coupled receptor (GPCR) and epidermal growth factor (EGF) receptor (ErbB1) transactivation signaling to the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade. This was based upon clozapine induced initial down-regulation and delayed ErbB1 mediated activation of the cortical and striatal ERK response in vivo distinct from other APDs. This study investigated if modulation of the ErbB1-ERK1/2 pathway by clozapine, olanzapine and haloperidol affected expression of the ERK substrates p90RSK and c-FOS, factors that regulate transcription of proteins associated with neuroplasticity and synapse formation in C57Bl/6 mice. In cortex and striatum, acute clozapine treatment induced biphasic p90RSK phosphorylation via MEK that paralleled ERK phosphorylation independent of EGF receptor blockade. By contrast, olanzapine and haloperidol caused p90RSK phosphorylation that was not concomitant with ERK signaling over a 24-hour period. For c-FOS, clozapine elevated expression 24h after administration, a timeframe consistent with ERK activation at 8h. Alternatively, haloperidol stimulation of c-FOS levels limited to the striatum was in accord with direct transcriptional regulation through ERK. The unique spatio-temporal expression of downstream nuclear markers of the ErbB1-ERK pathway invoked by clozapine may contribute to its effectiveness in treatment resistant schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 143 | Neuropsychobiology 2013 -1 68: 139-45 |
| PMID | 24051542 |
| Title | Facial affect recognition performance and event-related potentials in violent and non-violent schizophrenia patients. |
| Abstract | We investigated whether male inpatients with schizophrenia and a history of hands-on violent offences (forensic schizophrenic, FOS) are more impaired in emotion recognition than matched schizophrenia patients without any history of violence (general psychiatric schizophrenic, GPS). This should become apparent in performance in psychometry and in scalp event-related brain potentials (ERPs) evoked by pictures of facial affect. FOS and GPS (each n = 19) were matched concerning age, intelligence, comorbid addiction, medication and illness duration. FOS revealed significantly poorer affect recognition (AR) performance, especially of neutral and fear stimuli. Analysis of ERPs revealed a significant interaction of hemisphere, electrode position and group of the N250 component. Post hoc analysis of group effect showed significantly larger amplitudes in FOS at FC3. These results support the hypothesis that in FOS emotional faces are more salient and evoke higher arousal. Larger impairment in AR performance combined with higher salience and arousal may contribute to the occurrence of violent acts in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 144 | Eur. J. Neurosci. 2013 Nov 38: 3465-75 |
| PMID | 24103016 |
| Title | Functional integrity of the habenula is necessary for social play behaviour in rats. |
| Abstract | During post-weaning development, a marked increase in peer-peer interactions is observed in mammals, including humans, which is signified by the abundance of social play behaviour. Social play is highly rewarding, and known to be modulated through monoaminergic neurotransmission. Recently, the habenula has received widespread attention because of its role in the regulation of monoaminergic neurotransmission as well as in a variety of emotional and cognitive functions. Therefore, in the present study, we investigated the involvement of the habenula in social play behaviour. Using the neuronal activity maker c-FOS, we showed that the habenula was activated after 24 h of social isolation in adolescent rats, and that a subsequent social play interaction reduced c-FOS activity in the medial part of the lateral habenula. This suggested that habenula activity modulated the aversive properties of social isolation, which was alleviated by the positive effects of social play. Furthermore, after functional inactivation of the habenula, using a mixture of the GABA receptor agonists baclofen and muscimol, social play behaviour was markedly reduced, whereby responsiveness to play solicitation was more sensitive to habenula inactivation than play solicitation itself. Together, our data indicate an important role for the habenula in the processing of positive (i.e., social play behaviour) and negative (i.e., social isolation) social information in adolescent rats. Altered habenula function might therefore be related to the social impairments in childhood and adolescent psychiatric disorders such as autism, attention deficit/hyperactivity disorder and early-onset schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 145 | Int. J. Neuropsychopharmacol. 2013 Nov 16: 2145-63 |
| PMID | 23809188 |
| Title | Disruption of thalamocortical activity in schizophrenia models: relevance to antipsychotic drug action. |
| Abstract | Non-competitive NMDA receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to evoke the symptoms of the illness. Likewise, serotonergic hallucinogens, acting on 5-HT(2A) receptors, induce perceptual and behavioural alterations possibly related to psychotic symptoms. The neurobiological basis of these alterations is not fully elucidated. Data obtained in recent years revealed that the NMDA receptor antagonist phencyclidine (PCP) and the serotonergic hallucinogen 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane; DOI) produce a series of common actions in rodent prefrontal cortex (PFC) that may underlie psychotomimetic effects. Hence, both agents markedly disrupt PFC function by altering pyramidal neuron discharge (with an overall increase) and reducing the power of low frequency cortical oscillations (LFCO; < 4 Hz). In parallel, PCP increased c-FOS expression in excitatory neurons of various cortical areas, the thalamus and other subcortical structures, such as the amygdala. Electrophysiological studies revealed that PCP altered similarly the function of the centromedial and mediodorsal nuclei of the thalamus, reciprocally connected with PFC, suggesting that its psychotomimetic properties are mediated by an alteration of thalamocortical activity (the effect of DOI was not examined in the thalamus). Interestingly, the observed effects were prevented or reversed by the antipsychotic drugs clozapine and haloperidol, supporting that the disruption of PFC activity is intimately related to the psychotomimetic activity of these agents. Overall, the present experimental model can be successfully used to elucidate the neurobiological basis of schizophrenia symptoms and to examine the potential antipsychotic activity of new drugs in development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 146 | Neurosci. Lett. 2013 Aug 549: 97-102 |
| PMID | 23806600 |
| Title | Effect of blonanserin on methamphetamine-induced disruption of latent inhibition and c-Fos expression in rats. |
| Abstract | To clarify the psychopharmacological profile of blonanserin, a novel antipsychotic, we examined its effect on the methamphetamine-induced disruption of latent inhibition (LI) and the neural activation related to this effect in rats. To evaluate the LI, we used a conditioned emotional response in which a tone (conditioned stimulus) was paired with a mild foot shock (unconditioned stimulus). This paradigm was presented to rats licking water. Methamphetamine-induced (1.0mg/kg, i.p.) disruption of LI was significantly improved by the administration of a higher dose (3.0mg/kg, i.p.) of blonanserin and tended to be improved by 1.0-mg/kg blonanserin and 0.2-mg/kg haloperidol but not by a lower dose (0.3mg/kg) of blonanserin. Immunohistochemical examination showed blonanserin (3.0mg/kg, i.p.) increased c-FOS expression in the shell area but not in the core area of the nucleus accumbens while methamphetamine (3.0mg/kg, i.p.) produced the opposite expression pattern. Blonanserin also increased the number of c-FOS expressions in the central amygdala nucleus but not in the basolateral amygdala nucleus or the prefrontal cortex. Blonanserin ameliorates the methamphetamine-induced disruption of LI, as other antipsychotics do, and a neuronal activation and/or modulation of neurotransmission in the nucleus accumbens is related to the disruption of LI by methamphetamine and to its amelioration by blonanserin. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 147 | Schizophr. Res. 2013 Jun 147: 24-31 |
| PMID | 23566496 |
| Title | Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. |
| Abstract | schizophrenia (SZ) is a progressive, neuropsychiatric disorder associated with cognitive impairment. A number of brain alterations have been linked to cognitive impairment, including neuroinflammation, excitotoxicity, increased arachidonic acid (AA) signaling and reduced synaptic protein. On this basis, we tested the hypothesis that SZ pathology is associated with these pathological brain changes. To do this, we examined postmortem frontal cortex from 10 SZ patients and 10 controls and measured protein and mRNA levels of cytokines, and astroglial, microglial, neuroinflammatory, excitotoxic, AA cascade, apoptotic and synaptic markers. Mean protein and mRNA levels of interleukin-1?, tumor necrosis factor-?, glial acidic fibrillary protein (GFAP), a microglial marker CD11b, and nuclear factor kappa B subunits were significantly increased in SZ compared with control brain. Protein and mRNA levels of cytosolic and secretory phospholipase A2 and cyclooxygenase also were significantly elevated. N-methyl-d-aspartate receptor subunits 1 and 2B, inducible nitric oxide synthase and c-FOS were not significantly different. In addition, reduced protein and mRNA levels of brain-derived neurotrophic factor, synaptophysin and drebrin were found in SZ compared with control frontal cortex. Increased neuroinflammation and AA cascade enzyme markers with synaptic protein loss could promote disease progression and cognitive defects in SZ patients. Drugs that downregulate these changes might be considered for new therapies in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 148 | Synapse 2013 Sep 67: 553-67 |
| PMID | 23447367 |
| Title | Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats. |
| Abstract | Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine-related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5-day withdrawal period. In addition, c-FOS, FOSB/?FOSB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c-FOS expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FOSB/?FOSB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 149 | J. Neurosci. Res. 2013 May 91: 634-41 |
| PMID | 23404493 |
| Title | Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia. |
| Abstract | Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia-like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well-established model for schizophrenia-like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5-HT2A Rs. As a measure of 5-HT2A R functionality, we used the 5-HT2A R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response (HTR) and mRNA expression of the immediate-early genes (IEGs) activity-related cytoskeletal associated-protein (Arc), c-FOS, and early growth response protein 2 (egr-2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5-day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5-HT2A R binding. Also, binding of the 5-HT1A R and the 5-HT transporter was unaffected. Finally, basal mRNA level of Arc was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5-HT2A R could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 150 | Eur Neuropsychopharmacol 2013 Nov 23: 1516-29 |
| PMID | 23357084 |
| Title | Imaging brain gene expression profiles by antipsychotics: region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol. |
| Abstract | Induction of motor disorders is considered the clinical landmark differentiating typical from atypical antipsychotics, and has been mainly correlated to dopamine D2 receptors blockade in striatum. This view is challenged by benzamides, such as amisulpride, which display low liability for motor side effects despite being D2/D3 receptors high-affinity blocking agents. These effects have been explained with the prominent presynaptic action of amisulpride or with the fast dissociation at D2 receptors, but there is scarce information on the effects of amisulpride on postsynaptic signaling. We carried out a molecular imaging study of gene expression after acute administration of haloperidol (0.8 mg/kg), amisulpride (10 or 35 mg/kg), or vehicle, focusing on postsynaptic genes that are key regulators of synaptic plasticity, such as Arc, c-FOS, Zif-268, Norbin, Homer. The last one has been associated to schizophrenia both in clinical and preclinical studies, and is differentially induced by antipsychotics with different D2 receptors affinity. Topography of gene expression revealed that amisulpride, unlike haloperidol, triggers transcripts expression peak in medial striatal regions. Correlation analysis of gene expression revealed a prevalent correlated gene induction within motor corticostriatal regions by haloperidol and a more balanced gene induction within limbic and motor corticostriatal regions by amisulpride. Despite the selective dopaminergic profile of both compounds, our results demonstrated a differential modulation of postsynaptic molecules by amisulpride and haloperidol, the former impacting preferentially medial regions of striatum whereas the latter inducing strong gene expression in lateral regions. Thus, we provided a possible molecular profile of amisulpride, putatively explaining its "atypical atypicality". |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 151 | Psychopharmacology (Berl.) 2013 May 227: 251-61 |
| PMID | 23274507 |
| Title | Involvement of spinal 5-HT1A receptors in isolation rearing-induced hypoalgesia in mice. |
| Abstract | Isolation rearing in rodents causes not only abnormal behaviors which resemble the clinical symptoms of schizophrenia but also hypoalgesia in thermal nociception models. However, the mechanism of the hypoalgesia is not known. The present study investigated the effect of isolation rearing on acute pain and the descending pain inhibitory pathways in mice. Rearing in isolation for 6 weeks from post-weaning reduced pain sensitivity in the hot plate test and acetic acid-induced writhing test. Isolation rearing also reduced the intraplantar capsaicin-induced licking behavior. Capsaicin increased c-FOS expression, a neuronal activity marker, in the spinal cord and primary somatosensory cortex both in group- and isolation-reared mice, but this effect did not differ between groups. On the other hand, c-FOS expression in the anterior cingulate cortex, periaqueductal gray matter, and rostral ventromedial medulla, but not in the spinal cord or somatosensory cortex, was enhanced by isolation rearing. Systemic administration of WAY100635 (serotonin (5-HT)1A receptor antagonist), but not of ketanserin (5-HT2 receptor antagonist), prazosin (?1-adrenoceptor antagonist), or yohimbine (?2-adrenoceptor antagonist), attenuated isolation rearing-induced hypoalgesia in capsaicin-induced licking behavior. Attenuation of isolation rearing-induced hypoalgesia was also observed following the intrathecal injection of WAY100635. Naloxone, an opioid receptor antagonist, did not affect the hypoalgesia in isolation-reared mice. These findings suggest that isolation rearing causes hypoalgesia in mouse models of acute pain and imply that the spinal 5-HT1A receptor activation probably through descending serotonergic inhibitory pathway is involved in isolation rearing-induced hypoalgesia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 152 | Behav. Brain Res. 2013 Jan 237: 348-56 |
| PMID | 23069005 |
| Title | Deficits in trace fear memory in a mouse model of the schizophrenia risk gene TCF4. |
| Abstract | The basic helix-loop-helix (bHLH) transcription factor TCF4 was confirmed in the combined analysis of several large genome-wide association studies (GWAS) as one of the rare highly replicated significant schizophrenia (SZ) susceptibility genes in large case-control cohorts. Focused genetic association studies showed that TCF4 influences verbal learning and memory, and modulates sensorimotor gating. Mice overexpressing Tcf4 in the forebrain (Tcf4tg) display cognitive deficits in hippocampus-dependent learning tasks and impairment of prepulse inhibition, a well-established endophenotype of SZ. The spectrum of cognitive deficits in SZ subjects, however, is broad and covers attention, working memory, and anticipation. Collectively, these higher order cognitive processes and the recall of remote memories are thought to depend mainly on prefrontal cortical networks. To further investigate cognitive disturbances in Tcf4tg mice, we employed the trace fear conditioning paradigm that requires attention and critically depends on the anterior cingulate cortex (ACC). We show that Tcf4tg mice display deficits in recent and remote trace fear memory and are impaired at anticipating aversive stimuli. We also assessed mRNA expression of the neuronal activity-regulated gene FOS in the ACC and hippocampus. Upon trace conditioning, FOS expression is reduced in Tcf4tg mice as compared to controls, which parallels cognitive impairments in this learning paradigm. Collectively, these data indicate that the reduced cognitive performance in Tcf4tg mice includes deficits at the level of attention and behavioral anticipation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 153 | Neuropharmacology 2013 Feb 65: 39-47 |
| PMID | 23022048 |
| Title | Inhibition of GABA synthesis in the prefrontal cortex increases locomotor activity but does not affect attention in the 5-choice serial reaction time task. |
| Abstract | Attention deficits are a core cognitive symptom of schizophrenia; the neuropathology underlying these deficits is not known. Attention is regulated, at least in part, by the prefrontal cortex (PFC), a brain area in which pathology of ?-aminobutyric acid (GABA) neurons has been consistently observed in post-mortem analysis of the brains of people with schizophrenia. Specifically, expression of the 67-kD isoform of the GABA synthesis enzyme glutamic acid decarboxylase (GAD67) is reduced in parvalbumin-containing fast-spiking GABA interneurons. Thus it is hypothesized that reduced cortical GABA synthesis and release may contribute to the attention deficits in schizophrenia. Here the effect of reducing cortical GABA synthesis with l-allylglycine (LAG) on attention was tested using three different versions of the 5-choice serial reaction time task (5CSRTT). Because 5CSRTT performance can be affected by locomotor activity, we also measured this behavior in an open field. Finally, the expression of FOS protein was used as an indirect measure of reduced GABA synthesis. Intra-cortical LAG (10 ?g/0.5 ?l/side) infusions increased FOS expression and resulted in hyperactivity in the open field. Intra-cortical LAG infusions did not affect attention in any version of the 5CSRTT. These results suggest that a general decrease in GABA synthesis is not sufficient to cause attention deficits. It remains to be tested whether a selective decrease in GABA synthesis in parvalbumin-containing GABA neurons could cause attention deficits. Decreased cortical GABA synthesis did increase locomotor activity; this may reflect the positive symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 154 | Naunyn Schmiedebergs Arch. Pharmacol. 2013 Feb 386: 107-24 |
| PMID | 23001156 |
| Title | Direct and indirect interactions of the dopamine D? receptor with glutamate pathways: implications for the treatment of schizophrenia. |
| Abstract | This article, based on original data as well as on previously reported preclinical and clinical data that are reviewed, describes direct and indirect interactions of the D(3) receptor with N-methyl-D-aspartate receptor (NMDA) signaling and their functional consequences and therapeutic implications for schizophrenia. D(3) receptor immunoreactivity at ultrastructural level with electron microscopy was identified at presumably glutamatergic, asymmetric synapses of the medium-sized spiny neurons of the nucleus accumbens. This finding supports the existence of a direct interaction of the D(3) receptor with glutamate, in line with previously described interactions with NMDA signaling involving Ca(2+)/calmodulin-dependent protein kinase II at post-synaptic densities (Liu et al. 2009). Indirect interactions of the D(3) receptor with glutamate could involve a negative control exerted by the D(3) receptor on mesocortical dopamine neurons and the complex regulation of the glutamatergic pyramidal cells by dopamine in the prefrontal cortex. This could be exemplified here by the regulation of pyramidal cell activity in conditions of chronic NMDA receptor blockade with dizocilpine (MK-801). BP897, a D(3) receptor-selective partial agonist, reversed the dysregulation of cortical c-FOS mRNA expression and pyramidal cell hyperexcitability, as measured by paired-pulse electrophysiology. At the behavioral level, blockade of the D(3) receptor, by known D(3) receptor antagonists or the novel D(3) receptor-selective antagonist F17141, produces antipsychotic-like effects in reversing hyperactivity and social interaction deficits induced by NMDA receptor blockade by MK-801 in mice. The glutamate-D(3) receptor interactions described here offer a conceptual framework for developing new D(3) receptor-selective drugs, which may appear as an original, efficacious, and safe way to potentially indirectly target glutamate in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 155 | Psychopharmacology (Berl.) 2013 Jan 225: 217-26 |
| PMID | 22842765 |
| Title | Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice. |
| Abstract | In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT(2A) receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [(3)H]Ketanserin binding and 5-HT ( 2A ) mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-FOS, which is induced by all 5-HT(2A) agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed. Head-twitch response was decreased and [(3)H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT ( 2A ) mRNA was reduced 1 day after chronic clozapine. Induction of c-FOS, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day). Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT(2A) receptor as a potential mechanism involved in these persistent therapeutic-like effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 156 | Schizophr Bull 2013 May 39: 692-702 |
| PMID | 22927669 |
| Title | Prior haloperidol, but not olanzapine, exposure augments the pursuit of reward cues: implications for substance abuse in schizophrenia. |
| Abstract | Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain's dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-FOS mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 157 | Eur. Psychiatry 2014 Jun 29: 304-6 |
| PMID | 24630741 |
| Title | Psychosis-proneness correlates with expression levels of dopaminergic genes. |
| Abstract | Psychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 158 | J. Med. Chem. 2014 Nov 57: 9578-97 |
| PMID | 25343529 |
| Title | Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: synthesis, biological characterization, and behavioral studies. |
| Abstract | Combination of dopamine D3 antagonism, serotonin 5-HT1A partial agonism, and antagonism at 5-HT2A leads to a novel approach to potent atypical antipsychotics. Exploitation of the original structure-activity relationships resulted in the identification of safe and effective antipsychotics devoid of extrapyramidal symptoms liability, sedation, and catalepsy. The potential atypical antipsychotic 5bb was selected for further pharmacological investigation. The distribution of c-FOS positive cells in the ventral striatum confirmed the atypical antipsychotic profile of 5bb in agreement with behavioral rodent studies. 5bb administered orally demonstrated a biphasic effect on the MK801-induced hyperactivity at dose levels not able to induce sedation, catalepsy, or learning impairment in passive avoidance. In microdialysis studies, 5bb increased the dopamine efflux in the medial prefrontal cortex. Thus, 5bb represents a valuable lead for the development of atypical antipsychotics endowed with a unique pharmacological profile for addressing negative symptoms and cognitive deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 159 | Genes Brain Behav. 2014 Apr 13: 439-50 |
| PMID | 24612522 |
| Title | Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice. |
| Abstract | Reduced glutamic acid decarboxylase (GAD)67 expression may be causally involved in the development of social withdrawal in neuropsychiatric states such as autism, schizophrenia and bipolar disorder. In this study, we report disturbance of social behavior in male GAD67 haplodeficient mice. GAD67(+/-) mice, compared to GAD67(+/+) littermates, show reduced sociability and decreased intermale aggression, but normal nest building and urine marking behavior, as well as unchanged locomotor activity and anxiety-like behavior. Moreover, the mutants display a reduced sensitivity to both social and non-social odors, indicating a disturbance in the detection and/or processing of socially relevant olfactory stimuli. Indeed, we observed reduced activation of the lateral septum, medial preoptic area, bed nucleus of the stria terminalis, medial and cortical amygdala upon exposure of GAD67(+/-) mice to social interaction paradigm, as indicated by c-FOS immunohistochemistry. These data suggest a disturbance of stimulus processing in the brain circuitry controlling social behavior in GAD67(+/-) mice, which may provide a useful model for studying the impact of a reduced GAD67 expression on alterations of social behavior related to neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 160 | Behav. Brain Res. 2014 Feb 259: 242-6 |
| PMID | 24269270 |
| Title | D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI. |
| Abstract | Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction, the serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-FOS mRNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating the cellular and behavioral effects of 5-HT2AR activation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 161 | BMC Neurosci 2014 -1 15: 30 |
| PMID | 24552586 |
| Title | Quetiapine and aripiprazole signal differently to ERK, p90RSK and c-Fos in mouse frontal cortex and striatum: role of the EGF receptor. |
| Abstract | Signaling pathways outside dopamine D2 receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia. One postulated mechanism causal to APD action may regulate synaptic plasticity and neuronal connectivity via the extracellular signal-regulated kinase (ERK) cascade that links G-protein coupled receptors (GPCR) and ErbB growth factor signaling, systems disturbed in schizophrenia. This was based upon our finding that the low D2 receptor affinity APD clozapine induced initial down-regulation and delayed epidermal growth factor receptor (EGFR or ErbB1) mediated activation of the cortical and striatal ERK response in vivo distinct from olanzapine or haloperidol. Here we map whether the second generation atypical APDs aripiprazole and quetiapine affect the EGFR-ERK pathway and its substrates p90RSK and c-FOS in mouse brain, given their divergent agonist and antagonist properties on dopaminergic transmission, respectively. In prefrontal cortex, aripiprazole triggered triphasic ERK phosphorylation that was EGFR-independent but had no significant effect in striatum. Conversely quetiapine did not alter cortical ERK signaling but elevated striatal ERK levels in an EGFR-dependent manner. Induction of ERK by aripiprazole did not affect p90RSK signaling but quetiapine decreased RSK phosphorylation within 1-hour of administration. The transcription factor c-FOS by comparison was a direct target of ERK phosphorylation induced by aripiprazole in cortex and quetiapine in striatum with protein levels in temporal alignment with that of ERK. These data indicate that aripiprazole and quetiapine signal to specific nuclear targets of ERK, which for quetiapine occurs via an EGFR-linked mechanism, possibly indicating involvement of this system in its action. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 162 | Eur. Psychiatry 2014 Jun 29: 304-6 |
| PMID | 24630741 |
| Title | Psychosis-proneness correlates with expression levels of dopaminergic genes. |
| Abstract | Psychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 163 | Brain Res. Bull. 2014 Sep 108: 60-6 |
| PMID | 25171958 |
| Title | Effect of acute asenapine treatment on Fos expression in the forebrain structures under normal conditions and mild stress preconditioning in the rat. |
| Abstract | Asenapine (ASE) is a novel atypical antipsychotic drug approved for the treatment of schizophrenia and bipolar disorder. Stress is an inseparable part of the human life, which may interfere with the therapeutic effect of different drugs. The aim of the present study was: (1) to delineate the quantitative and qualitative profiles of the ASE effect on FOS expression in the striatum, septum, nucleus accumbens, and the prefrontal cortex and (2) to find out whether a chronic unpredictable variable mild stress (CMS) preconditioning may modify the effect of acute ASE treatment. Stress paradigms included restrain, social isolation, crowding, swimming, and cold. The animals were exposed to CMS for 21 days and on the 22nd day received an injection of vehicle (saline 300 ?l/rat s.c.) or ASE (0.3mg/kg s.c.). They were sacrificed 90 min after the treatments. FOS protein was visualized by avidin biotin peroxidase (ABC). Four groups of animals were investigated: controls+vehicle, controls+ASE, CMS+vehicle, and CMS+ASE. The number of FOS labeled neurons was calculated per total investigated area, which was selective for each structure, and also recalculated per unified sector. ASE treatment induced significant and very similar increase of the FOS expression in both ASE control and ASE CMS animals in comparison with saline control and CMS ones. Moreover, ASE induced regional differences in the number of FOS-positive neurons. In both ASE groups most pronounced response in the number of FOS profiles occurred in the dorsolateral striatum, ventrolateral septum, shell of the nucleus accumbens, and the medial prefrontal cortex. Mild FOS response was seen in the dorsomedial and ventromedial striatum and core of the nucleus accumbens. No response was seen in the dorsolateral septum. The present paper demonstrates for the first time the character of the FOS distribution in the forebrain structures induced by acute ASE treatment as well as ASE response to 21 days CMS preconditioning. The study provides an important comparative background that may help in the further understanding of the effect of ASE on the brain activation as well as its responsiveness to CMS challenges. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 164 | Int. J. Dev. Neurosci. 2014 Nov 38: 30-5 |
| PMID | 25102410 |
| Title | Prenatal stress increases the striatal and hippocampal expression of correlating c-FOS and serotonin transporters in murine offspring. |
| Abstract | Prenatal stress (PS) is a known risk factor for several psychiatric diagnoses, including schizophrenia, attention deficit hyperactivity disorder, autism, anxiety, and depression which have been associated with serotonin transporter (SERT) dysregulation. Moreover, long-term effects in animal models associate with higher levels of immediate early genes, e.g. c-FOS (up-regulated in response to neuronal activity), in the brain of PS offspring. We therefore quantified the expression of both protein related mRNAs in adolescent BALB/c mice subjected to mild auditory stress on two separate days in mid gestation. SERT and c-FOS consistently correlated in most brain regions of PS mice and controls. Moreover, two-way ANOVAs revealed concomitantly increased levels of proteins, as well as of FOSL1 and FOSL2 mRNA, especially in the striatum and hippocampus of the PS offspring. Sex affected only and less consistently mRNA expression, yet interacted with PS, demonstrating that glucocorticoid receptor mRNA expression decreased in PS males but increased in PS females compared to the respective controls. This first finding of a correlation between SERT and c-FOS protein expression affected by PS, together with related mRNAs, may be considered a new target for behavioral and treatment studies in offspring. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 165 | Eur Neuropsychopharmacol 2014 Sep 24: 1524-33 |
| PMID | 25088904 |
| Title | Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice. |
| Abstract | Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with constitutive activity involved in cellular architecture, gene expression, cell proliferation, fate decision and apoptosis, among others. GSK-3 expression is particularly high in brain where it may be involved in neurological and psychiatric disorders such as Alzheimer?s disease, bipolar disorder and major depression. A link with schizophrenia is suggested by the antipsychotic drug-induced GSK-3 regulation and by the involvement of the Akt/GSK-3 pathway in dopaminergic neurotransmission. Taking advantage of the previous development of dominant negative GSK-3 transgenic mice (Tg) showing a selective reduction of GSK-3 activity in forebrain neurons but not in dopaminergic neurons, we explored the relationship between GSK-3 and dopaminergic neurotransmission in vivo. In microdialysis experiments, local quinpirole (DA D2-R agonist) in dorsal striatum reduced dopamine (DA) release significantly less in Tg mice than in wild-type (WT) mice. However, local SKF-81297 (selective DA D1-R agonist) in dorsal striatum reduced DA release equally in both control and Tg mice indicating a comparable function of DA D1-R in the direct striato-nigral pathway. Likewise, systemic quinpirole administration - acting preferentially on presynaptic DA D2- autoreceptors to modulate DA release-reduced striatal DA release similarly in both control and Tg mice. Quinpirole reduced locomotor activity and induced c-FOS expression in globus pallidus (both striatal DA D2-R-mediated effects) significantly more in WT than in Tg mice. Taking together, the present results show that dominant negative GSK-3 transgenic mice show reduced DA D2-R-mediated function in striatum and further support a link between dopaminergic neurotransmission and GSK-3 activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 166 | Eur. J. Pharmacol. 2014 Oct 740: 669-75 |
| PMID | 24967534 |
| Title | Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain. |
| Abstract | Dopamine D3 receptors are a major target for drug discovery programs related to psychiatric disorders such as schizophrenia. The ability of a compound to occupy significant levels of D3 receptors is important for achieving therapeutic efficacy in both pre-clinical and clinical settings. Here we attempt to characterise antipsychotic drug-effects at D3 receptors by measuring receptor occupancy via ex-vivo [3H]7-OH-DPAT autoradiography, and further validating this outcome via analysis of FOS-like immunoreactivity (FOS-LI) in the rat major islands of Calleja (ICjM), a brain structure with high D3 expression. Rats were treated subcutaneously with haloperidol (0.04 mg/kg), clozapine (20 mg/kg) and olanzapine (0.63 mg/kg), the selective D2 antagonist L-741626 (2.5 mg/kg) and the selective D3 antagonist SB-277011-A (10 mg/kg). Doses were based on levels of D2 occupancy considered clinically relevant (60-80%). When measuring D3 occupancy, clozapine and SB-277011-A displayed meaningful levels of occupancy (60% and 77%, respectively), haloperidol and olanzapine showed limited occupancy (16% and 27%, respectively), whereas L-741626 showed no occupancy. There were no significant changes in ICjM FOS-LI after L-741626 and haloperidol treatment, minor but significant increases after olanzapine treatment, whereas highly significant increases were seen with SB-277011-A and clozapine. Additionally, pre-treating clozapine with the D1 antagonist SCH23390 caused a significant, albeit non-complete, reduction in FOS-LI, highlighting the D1 agonist property of clozapine. In conclusion, it appears that drugs occupying >50% D3 receptors produce robust increases in ICjM FOS-LI. This study may help to identify the appropriate D3 receptor antagonists that have the potential to be tested in the clinic. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 167 | PLoS ONE 2014 -1 9: e89153 |
| PMID | 24586556 |
| Title | Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. |
| Abstract | Accumulating evidence from human genetic studies implicates the pituitary adenylate cyclase-activating polypeptide (PACAP) gene as a risk factor for psychiatric disorders, including schizophrenia and stress-related diseases. Mice with homozygous disruption of the PACAP gene display profound behavioral and neurological abnormalities that are ameliorated with the atypical antipsychotic and dopamine D2 and serotonin (5-HT)2 antagonist risperidone and the 5-HT2 receptor antagonist ritanserin; however, the underlying mechanisms remain unknown. Here, we investigated if PACAP heterozygous mutant (PACAP(+/-)) mice, which appear behaviorally normal, are vulnerable to aversive stimuli. PACAP(+/-) mice were administered a 5-HT2 receptor agonist, (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), a hallucinogenic drug, and their responses were compared with the littermate wild-type mice. After DOI injection, PACAP(+/-) mice showed increased head-twitch responses, while their behavior was normal after saline. DOI induced deficits in sensorimotor gating, as determined by prepulse inhibition, specifically in PACAP(+/-) mice. However, other 5-HT2 receptor-dependent responses, such as corticosterone release and hypothermia, were similarly observed in PACAP(+/-) and wild-type mice. c-FOS expression analysis, performed in various brain regions, revealed that the DOI-induced increase in the number of c-FOS-positive cells was more pronounced in 5-HT2A receptor-negative cells in the somatosensory cortex in PACAP(+/-) mice compared with wild-type mice. These results indicate that PACAP(+/-) mice exhibit specific vulnerability to DOI-induced deficits in cortical sensory function, such as exaggerated head-twitch responses and sensorimotor gating deficits. Our findings provide insight into the neural mechanisms underlying impaired behavioral responses in which 5-HT2 receptors are implicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 168 | Neuropharmacology 2014 Jun 81: 215-23 |
| PMID | 24534112 |
| Title | N-acetylcysteine modulates hallucinogenic 5-HT(2A) receptor agonist-mediated responses: behavioral, molecular, and electrophysiological studies. |
| Abstract | N-acetylcysteine (NAC) has been reported to reverse the psychotomimetic effects in the rodent phencyclidine model of psychosis and shown beneficial effects in treating patients with schizophrenia. The effect of NAC has been associated with facilitating the activity of cystine-glutamate antiporters on glial cells concomitant with the release of non-vesicular glutamate, which mainly stimulates the presynaptic metabotropic glutamate receptor subtype 2 receptors (mGluR2). Recent evidence demonstrated that functional interactions between serotonin 5-HT2A receptor (5-HT(2A)R) and mGluR2 are responsible to unique cellular responses when targeted by hallucinogenic drugs. The present study determined the effects of NAC on hallucinogenic 5-HT(2A)R agonist (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-elicited behavioral and molecular responses in mice and DOI-evoked field potentials in the mouse cortical slices. NAC significantly attenuated DOI-induced head twitch response and expression of c-FOS and Egr-2 in the infralimbic and motor cortex and suppressed the increase in the frequency of excitatory field potentials elicited by DOI in the medial prefrontal cortex. In addition, the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine (CPG) and the mGluR2 antagonist LY341495 reversed the suppressing effects of NAC on DOI-induced head twitch and molecular responses and increased frequency of excitatory field potentials, supporting that NAC attenuates the 5-HT(2A)R-mediated hallucinogenic effects via increased activity of cystine-glutamate antiporter followed by activation of mGluR2 receptors. These findings implicate NAC as a potential therapeutic agent for hallucinations and psychosis associated with hallucinogen use and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 169 | Behav. Brain Res. 2014 Apr 262: 74-83 |
| PMID | 24406716 |
| Title | 7-Nitroindazole blocks the prepulse inhibition disruption and c-Fos increase induced by methylphenidate. |
| Abstract | The dopamine and nitric oxide (NO) interaction on sensorimotor gating modulation measured through the prepulse inhibition (PPI), has been described recently. The PPI impairment has been reported in several neuropsychiatric conditions, particularly in schizophrenia. We previously demonstrated that NO inhibitors, similarly to the antipsychotic drugs, attenuate the disruptive effect of amphetamine or its analogue methylphenidate in the PPI response. Our aim was to determine if the known expression of the neuronal activity marker c-FOS induced by methylphenidate may be modified by NO inhibition. Mice were treated with the PPI-disruptive dose of methylphenidate (30 mg/kg) preceded by pretreatment with saline, or the dose of preferential neuronal NO inhibitor 7-Nitroindazole (7NI; 10 mg/kg) which promotes PPI recovery. Acute treatment with methylphenidate at dose that caused PPI disruption induced a robust increase in the number of c-FOS-positive cells in the cingulate and motor cortex, dorsal, dorsolateral, and ventrolateral striatum, nucleus accumbens core and shell, and basolateral amygdala. In the animals which presented PPI recovery through 7NI pretreatment, the c-FOS increase induced by methylphenidate was significantly reduced in the cingulate cortex (rostral level), striatum, mainly dorsal and ventrolateral, nucleus accumbens (core and shell), and in the basolateral amygdala. Our results suggest that 7NI effects appear to be related to its ability to prevent the activation of specific brain areas, including nucleus accumbens and amygdala, counteracting the stimulant effects of methylphenidate in these regions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 170 | Curr. Mol. Med. 2015 -1 15: 222-36 |
| PMID | 25817857 |
| Title | Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801. |
| Abstract | Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 ?g/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose-dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-FOS induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK-801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 171 | PLoS ONE 2015 -1 10: e0116686 |
| PMID | 25658856 |
| Title | Altered gene expression in schizophrenia: findings from transcriptional signatures in fibroblasts and blood. |
| Abstract | Whole-genome expression studies in the peripheral tissues of patients affected by schizophrenia (SCZ) can provide new insight into the molecular basis of the disorder and innovative biomarkers that may be of great utility in clinical practice. Recent evidence suggests that skin fibroblasts could represent a non-neural peripheral model useful for investigating molecular alterations in psychiatric disorders. A microarray expression study was conducted comparing skin fibroblast transcriptomic profiles from 20 SCZ patients and 20 controls. All genes strongly differentially expressed were validated by real-time quantitative PCR (RT-qPCR) in fibroblasts and analyzed in a sample of peripheral blood cell (PBC) RNA from patients (n = 25) and controls (n = 22). To evaluate the specificity for SCZ, alterations in gene expression were tested in additional samples of fibroblasts and PBCs RNA from Major Depressive Disorder (MDD) (n = 16; n = 21, respectively) and Bipolar Disorder (BD) patients (n = 15; n = 20, respectively). Six genes (JUN, HIST2H2BE, FOSB, FOS, EGR1, TCF4) were significantly upregulated in SCZ compared to control fibroblasts. In blood, an increase in expression levels was confirmed only for EGR1, whereas JUN was downregulated; no significant differences were observed for the other genes. EGR1 upregulation was specific for SCZ compared to MDD and BD. Our study reports the upregulation of JUN, HIST2H2BE, FOSB, FOS, EGR1 and TCF4 in the fibroblasts of SCZ patients. A significant alteration in EGR1 expression is also present in SCZ PBCs compared to controls and to MDD and BD patients, suggesting that this gene could be a specific biomarker helpful in the differential diagnosis of major psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 172 | Pharmacol. Biochem. Behav. 2015 Nov 138: 14-9 |
| PMID | 26363311 |
| Title | Atypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin. |
| Abstract | Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of FOS protein expression revealed that both AD-6048 and HAL significantly increased FOS expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal FOS expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 173 | Neuropharmacology 2015 Dec 99: 379-86 |
| PMID | 26256420 |
| Title | Phosphodiesterase 10A inhibitor, MP-10 (PF-2545920), produces greater induction of c-Fos in dopamine D2 neurons than in D1 neurons in the neostriatum. |
| Abstract | Studies described here tested the hypothesis that phosphodiesterase 10A inhibition by a selective antagonist, MP-10, activates the dopamine D2 receptor expressing medium spiny neurons to a greater extent than the D1 receptor expressing neurons. We used regional pattern of c-FOS induction in the neostriatal subregions of rodents and direct assessment of D1-positive and -negative neurons in the DRd1a-tdTomato mice for the purpose. MP-10 (1, 3, 10 or 30 mg/kg, PO) dose-dependently increased c-FOS immunopositive nuclei in all regions of neostriatum. However, the effect was statistically greater in the dorsolateral striatum, a region known to be activated preferentially by the D2 antagonism, than the D1-activated dorsomedial striatum. The D2 antagonist, haloperidol (0.3, 1, or 3 mg/kg, PO) produced an identical, regional pattern of c-FOS induction favoring the dorsolateral striatum of the rat. In contrast, the D1 agonist, SKF82958 (0.5, 1, or 2 mg/kg, PO), induced greater expression of c-FOS in the dorsomedial striatum. The C57Bl/6 mouse also showed regionally preferential c-FOS activation by haloperidol (2 mg/kg, IP) and SKF82858 (3 mg/kg, IP). In the Drd1a-tdTomato mice, MP-10 (3 or 10 mg/kg, IP) increased c-FOS immunoreactivity in both types of neurons, the induction was greater in the D1-negative neurons. Taken together, both the regional pattern of c-FOS induction in the striatal sub-regions and the greater induction of c-FOS in the D1-negative neurons indicate that PDE10A inhibition produces a small but significantly greater activation of the D2-containing striatopallidal pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 174 | Folia Biol. (Praha) 2015 -1 61: 110-5 |
| PMID | 26213855 |
| Title | Effect of Asenapine on the Activity of Hypocretin Neurons in Normal and Unpredictable Mild Stress Preconditioned Rats. |
| Abstract | Asenapine (ASE) is a novel atypical antipsychotic used in schizophrenia treatment. Here, the effect of ASE on FOS expression in hypocretin (Hcrt) neurons in medial and lateral portions of the lateral hypothalamus (LH) and the effect of chronic unpredictable variable mild stress (CMS) preconditioning were studied. CMS consisted of restraint, social isolation, crowding, swimming, and cold and lasted 21 days. The rats were sacrificed on day 22, 90 min after a single injection of vehicle (saline 300 ?l/rat subcutaneously--s.c.) or ASE (0.3 mg/kg s.c.). Control (CON), ASE, CMS, and CMS+ASE groups were used. FOS protein was visualized by the avidin biotin peroxidase technique, while Hcrt perikarya by fluorescent dye. FOS/Hcrt co-localizations were evaluated under parallel light and fluorescent illuminations. In the single FOS expression assessment, the FOS number was significantly higher in the medial in comparison with the lateral LH portion in each group. No differences in FOS amount were observed between the individual groups within the medial and lateral LH portions. In the FOS/Hcrt co-localization assessments, ASE significantly reduced the number of FOS/Hcrt neurons in the medial, but not lateral, LH portion in ASE and CMS+ASE groups. CMS only slightly contributed to the inhibitory effect of ASE in the CMS+ASE groups. The present data show as the first that ASE may reduce the activity of Hcrt cells in the medial LH portion, which might correspond with the relatively low weight gain liability of ASE. CMS preconditioning did not significantly interfere with this impact of ASE. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 175 | Eur. J. Neurosci. 2015 Sep 42: 2335-45 |
| PMID | 26118640 |
| Title | Mouse pups lacking collapsin response mediator protein 4 manifest impaired olfactory function and hyperactivity in the olfactory bulb. |
| Abstract | Members of the collapsin response mediator protein (CRMP) family are reported to be involved in the pathogenesis of various neuronal disorders, including schizophrenia and autism. One of them, CRMP4, is reported to participate in aspects of neuronal development, such as axonal guidance and dendritic development. However, no physiological or behavioral phenotypes in Crmp4 knockout (Crmp4-KO) mice have been identified, making it difficult to elucidate the in vivo roles of CRMP4. Focusing on the olfaction process because of the previous study showing strong expression of Crmp4 mRNA in the olfactory bulb (OB) during the early postnatal period, it was aimed to test the hypothesis that Crmp4-KO pups would exhibit abnormal olfaction. Based on measurements of their ultrasonic vocalizations, impaired olfactory ability in Crmp4-KO pups was found. In addition, c-FOS expression, a marker of neuron activity, revealed hyperactivity in the OB of Crmp4-KO pups compared with wild-types following exposure to an odorant. Moreover, the mRNA and protein expression levels of glutamate receptor 1 (GluR1) and 2 (GluR2) were exaggerated in Crmp4-KO pups relative to other excitatory and inhibitory receptors and transporters, raising the possibility that enhanced expression of these excitatory receptors contributes to the hyperactivity phenotype and impairs olfactory ability. This study provides evidence for an animal model for elucidating the roles of CRMP4 in the development of higher brain functions as well as for elucidating the developmental regulatory mechanisms controlling the activity of the neural circuitry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 176 | Neurobiol. Dis. 2015 Oct 82: 176-84 |
| PMID | 26093170 |
| Title | Adolescent cannabis exposure interacts with mutant DISC1 to produce impaired adult emotional memory. |
| Abstract | Cannabis is an increasingly popular and controversial drug used worldwide. Cannabis use often begins during adolescence, a highly susceptible period for environmental stimuli to alter functional and structural organization of the developing brain. Given that adolescence is a critical time for the emergence of mental illnesses before full-onset in early adulthood, it is particularly important to investigate how genetic insults and adolescent cannabis exposure interact to affect brain development and function. Here we show for the first time that a perturbation in disrupted in schizophrenia 1 (DISC1) exacerbates the response to adolescent exposure to delta-9-tetrahydrocannabinol (?(9)-THC), a major psychoactive ingredient of cannabis, consistent with the concept that gene-environment interaction may contribute to the pathophysiology of psychiatric conditions. We found that chronic adolescent treatment with ?(9)-THC exacerbates deficits in fear-associated memory in adult mice that express a putative dominant-negative mutant of DISC1 (DN-DISC1). Synaptic expression of cannabinoid receptor 1 (CB1R) is down-regulated in the prefrontal cortex, hippocampus, and amygdala, critical brain regions for fear-associated memory, by either expression of DN-DISC1 or adolescent ?(9)-THC treatment. Notably, elevation of c-FOS expression evoked by context-dependent fear memory retrieval is impaired in these brain regions in DN-DISC1 mice. We also found a synergistic reduction of c-FOS expression induced by cue-dependent fear memory retrieval in DN-DISC1 with adolescent ?(9)-THC exposure. These results suggest that alteration of CB1R-mediated signaling in DN-DISC1 mice may underlie susceptibility to detrimental effects of adolescent cannabis exposure on adult behaviors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 177 | Neuropharmacology 2015 Oct 97: 275-88 |
| PMID | 26051401 |
| Title | Maternal lipopolysaccharide treatment differentially affects 5-HT(2A) and mGlu2/3 receptor function in the adult male and female rat offspring. |
| Abstract | Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. However, it is still not fully understood which biochemical mechanisms are responsible for the emergence of neuropsychiatric symptoms following prenatal immune activation. The serotonin (5-hydroxytryptamine, 5-HT) and glutamate system have prominently been associated with the schizophrenia pathophysiology but also with the mechanism of antipsychotic drug actions. Here, we investigated the behavioral and cellular response to 5-HT2A and metabotropic glutamate (mGlu)2/3 receptor stimulation in male and female offspring born to lipopolysaccharide (LPS)-treated mothers. Additionally, we assessed protein expression levels of prefrontal 5-HT2A and mGlu2 receptors. Prenatally LPS-exposed male and female offspring showed locomotor hyperactivity and increased head-twitch behavior in response to the 5-HT2A receptor agonist DOI. In LPS-exposed male offspring, the mGlu2/3 receptor agonist LY379268 failed to reduce DOI-induced prepulse inhibition deficits. In LPS-males, the behavioral changes were further accompanied by enhanced DOI-induced c-FOS protein expression and an up-regulation of prefrontal 5-HT2A receptors. No changes in either 5-HT2A or mGlu2 receptor protein levels were found in female offspring. Our data support the hypothesis of an involvement of maternal infection during pregnancy contributing, at least partially, to the pathology of schizophrenia. Identifying biochemical alterations that parallel the behavioral deficits may help to improve therapeutic strategies in the treatment of this mental illness. Since most studies in rodents almost exclusively include male subjects, our data further contribute to elucidating possible gender differences in the effects of prenatal infection on 5-HT2A and mGlu2/3 receptor function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 178 | Neuropharmacology 2015 Dec 99: 256-63 |
| PMID | 26044638 |
| Title | The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents. |
| Abstract | Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-FOS, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 179 | Psychopharmacology (Berl.) 2015 Nov 232: 4085-97 |
| PMID | 25943167 |
| Title | PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments. |
| Abstract | N-methyl-D-aspartate receptor (NMDA-R) hypofunction has been proposed to account for the pathophysiology of schizophrenia. Thus, NMDA-R blockade has been used to model schizophrenia in experimental animals. Acute and repeated treatments have been successfully tested; however, long-term exposure to NMDA-R antagonists more likely resembles the core symptoms of the illness. To explore whether schizophrenia-related behaviors are differentially induced by acute and subchronic phencyclidine (PCP) treatment in mice and to examine the neurobiological bases of these differences. Subchronic PCP induced a sensitization of acute locomotor effects. Spontaneous alternation in a T-maze and novel object recognition performance were impaired after subchronic but not acute PCP, suggesting a deficit in working memory. On the contrary, reversal learning and immobility in the tail suspension test were unaffected. Subchronic PCP significantly reduced basal dopamine but not serotonin output in medial prefrontal cortex (mPFC) and markedly decreased the expression of tyrosine hydroxylase in the ventral tegmental area. Finally, acute and subchronic PCP treatments evoked a different pattern of c-FOS expression. At 1 h post-treatment, acute PCP increased c-FOS expression in many cortical regions, striatum, thalamus, hippocampus, and dorsal raphe. However, the increased c-FOS expression produced by subchronic PCP was restricted to the retrosplenial cortex, thalamus, hippocampus, and supramammillary nucleus. Four days after the last PCP injection, c-FOS expression was still increased in the hippocampus of subchronic PCP-treated mice. Acute and subchronic PCP administration differently affects neuronal activity in brain regions relevant to schizophrenia, which could account for their different behavioral effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 180 | Front Behav Neurosci 2015 -1 9: 74 |
| PMID | 25859195 |
| Title | Neural circuits containing olfactory neurons are involved in the prepulse inhibition of the startle reflex in rats. |
| Abstract | Many neuropsychiatric disorders, such as schizophrenia, have been associated with olfactory dysfunction and abnormalities in the prepulse inhibition (PPI) response to a startle reflex. However, whether these two abnormalities could be related is unclear. The present investigations were designed to determine whether theblockage of olfactory sensory input by zinc sulfate infusion in the olfactory naris (0.5 ml, 0.17 M, ZnE) can disturb the PPI response. Furthermore, a bilateral microinjection of lidocaine/MK801 in the olfactory bulb (OB) was administered to examine whether the blockage of olfactory sensory input could impair the PPI response. To identify the neural projection between olfaction and PPI-related areas, trans-synaptic retrograde tracing with the recombinant pseudorabies virus (PRV) was used. Our results demonstrated that blockage of olfactory sensory input could disturb olfactory behavior. In the function studies, we demonstrated that blockage of olfactory sensory input could impair the pre-pulse inhibition of the startle response following decreased c-FOS expression in relevant brain regions during the PPI responses. Furthermore, similar and more robust findings indicated that blockage of olfactory sensory input by microinjection of lidocaine/MK801 in the OB could impair the PPI response. In the circuit-level studies, we demonstrated that trans-synaptic retrograde tracing with PRV exhibited a large portion of labeled neurons in several regions of the olfactory cortices from the pedunculopontine tegmental nucleus (PPTg). Thus, these data suggest that the olfactory system participates in the PPI regulating fields and plays a role in the pre-pulse inhibition of the startle response in rats. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 181 | Recent Adv DNA Gene Seq 2015 -1 9: 51-7 |
| PMID | 25706621 |
| Title | Schizophrenia-associated Risk and Protective Variants of c-Fos Encoding Gene. |
| Abstract | Defects in synaptic plasticity play a key role in pathophysiology of schizophrenia. Pathomechanisms responsible for synaptic plasticity alterations in schizophrenia are very complicated and not well defined. Transcription factor c-FOS plays an important role in regulation of synaptic plasticity. In the present study we evaluated the association of rs7101 and rs1063169 single nucleotide polymorphisms (SNPs) of c-FOS encoding gene (FOS) with schizophrenia. A total of 604 DNA samples of schizophrenia-affected and healthy subjects of Armenian ancestry were genotyped using polymerase chain reaction with sequence-specific primers. Also, comparative determination of the blood levels of c-FOS protein in schizophrenia patients and controls was performed using the enzyme-linked immunosorbent assay. Potential interaction between protein level and genotypes as well as relationships between genotypes/protein level and clinical-demographic characteristics of schizophrenia patients were assessed. The results obtained demonstrated that mutant allele of FOS rs1063169 SNP is negatively associated with schizophrenia and may be nominated as a protective factor for this disorder. On the other hand, according to our results, the FOS rs7101T mutant allele is positively associated with schizophrenia and, therefore, may be considered as a risk factor for this disorder. In addition, decreased c-FOS plasma levels in schizophrenia patients compared to controls were found. In conclusion, the results of this study suggest that FOS is among the candidate genes of schizophrenia and that changes in the expression of c-FOS protein may contribute to molecular pathomechanisms of schizophrenia-related alterations in synaptic plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 182 | Eur Neuropsychopharmacol 2015 Apr 25: 566-82 |
| PMID | 25649681 |
| Title | Progressive recruitment of cortical and striatal regions by inducible postsynaptic density transcripts after increasing doses of antipsychotics with different receptor profiles: insights for psychosis treatment. |
| Abstract | Antipsychotics may modulate the transcription of multiple gene programs, including those belonging to postsynaptic density (PSD) network, within cortical and subcortical brain regions. Understanding which brain region is activated progressively by increasing doses of antipsychotics and how their different receptor profiles may impact such an activation could be relevant to better correlate the mechanism of action of antipsychotics both with their efficacy and side effects. We analyzed the differential topography of PSD transcripts by incremental doses of two antipsychotics: haloperidol, the prototypical first generation antipsychotic with prevalent dopamine D2 receptors antagonism, and asenapine, a second generation antipsychotic characterized by multiple receptors occupancy. We investigated the expression of PSD genes involved in synaptic plasticity and previously demonstrated to be modulated by antipsychotics: Homer1a, and its related interacting constitutive genes Homer1b/c and PSD95, as well as Arc, C-FOS and Zif-268, also known to be induced by antipsychotics administration. We found that increasing acute doses of haloperidol induced immediate-early genes (IEGs) expression in different striatal areas, which were progressively recruited by incremental doses with a dorsal-to-ventral gradient of expression. Conversely, increasing acute asenapine doses progressively de-recruited IEGs expression in cortical areas and increased striatal genes signal intensity. These effects were mirrored by a progressive reduction in locomotor animal activity by haloperidol, and an opposite increase by asenapine. Thus, we demonstrated for the first time that antipsychotics may progressively recruit PSD-related IEGs expression in cortical and subcortical areas when administered at incremental doses and these effects may reflect a fine-tuned dose-dependent modulation of the PSD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 183 | Neurosci. Res. 2016 Apr -1: -1 |
| PMID | 27091613 |
| Title | Distinct neuronal activation patterns are associated with PCP-induced social withdrawal and its reversal by the endocannabinoid-enhancing drug URB597. |
| Abstract | The fatty acid amide hydrolase inhibitor, URB597, an endocannabinoid enhancing drug, reverses social withdrawal in the sub-chronic PCP rat model of schizophrenia, but reduces social interaction (SI) in controls. To identify the anatomical substrates associated with PCP-induced social withdrawal and the contrasting effects of URB597 on SI in PCP- versus saline-treated rats, we analyzed SI-induced c-FOS expression in 28 brain areas relevant to schizophrenia and/or social behavior following vehicle or URB597 administration. In saline-treated rats, SI was accompanied by changes in c-FOS expression in the infralimbic and orbitofrontal cortices, dorsomedial caudate putamen, ventrolateral nucleus of the septum, dorsolateral periaqueductal gray (dlPAG) and central amygdala. Except for the dlPAG, these changes were not observed in PCP-treated rats or in saline-treated rats receiving URB597. In the dorsomedial part of the bed nucleus of the stria terminalis (dmBNST), SI-induced c-FOS expression was observed only in PCP-treated rats. Interestingly, URB597 in PCP-treated rats restored a similar c-FOS expression pattern as observed in saline-treated rats: activation of the orbitofrontal cortex, inhibition of the central amygdala and suppression of activation of the dmBNST. These data suggest that orbitofrontal cortex, central amygdala and dmBNST play a critical role in the reversal of PCP-induced social withdrawal by URB597. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 184 | Behav. Brain Res. 2016 Apr 309: 22-28 |
| PMID | 27131780 |
| Title | Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice. |
| Abstract | Cannabidiol (CBD) is a major non-psychoactive compound from Cannabis sativa plant. Given that CBD reduces psychotic symptoms without inducing extrapyramidal motor side-effects in animal models and schizophrenia patients, it has been proposed to act as an atypical antipsychotic. In addition, CBD reduced catalepsy induced by drugs with distinct pharmacological mechanisms, including the typical antipsychotic haloperidol. To further investigate this latter effect, we tested whether CBD (15-60mg/kg) would attenuate the catalepsy and c-FOS protein expression in the dorsal striatum induced by haloperidol (0.6mg/kg). We also evaluated if these effects occur through the facilitation of 5-HT1A receptor-mediated neurotransmission. For this, male Swiss mice were treated with CBD and haloperidol systemically and then subjected to the catalepsy test. Independent groups of animals were also treated with the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). As expected, haloperidol induced catalepsy throughout the experiments, an effect that was prevented by systemic CBD treatment 30min before haloperidol administration. Also, CBD, administered 2.5h after haloperidol, reversed haloperidol-induced catalepsy. Haloperidol also increased c-FOS protein expression in the dorsolateral striatum, an effect attenuated by previous CBD administration. CBD effects on catalepsy and c-FOS protein expression induced by haloperidol were blocked by the 5-HT1A receptor antagonist. We also evaluated the effects of CBD (60nmol) injection into the dorsal striatum on haloperidol-induced catalepsy. Similar to systemic administration, this treatment reduced catalepsy induced by haloperidol. Altogether, these results suggest that CBD acts in the dorsal striatum to improve haloperidol-induced catalepsy via postsynaptic 5-HT1A receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 185 | Psychopharmacology (Berl.) 2016 Jun 233: 2373-81 |
| PMID | 27095448 |
| Title | Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex. |
| Abstract | We previously reported that prenatal treatment with phencyclidine (PCP) induces glutamatergic dysfunction in the prefrontal cortex (PFC), leading to schizophrenia-like behavioral deficits in adult mice. However, little is known about the prenatal effect of PCP treatment on other types of neurons. We focused on ?-aminobutyric acid (GABA)-ergic interneurons and evaluated the effect of prenatal PCP exposure on the neurodevelopment of GABAergic interneurons in the PFC. PCP was administered at the dose of 10 mg/kg/day to pregnant dams from embryonic day 6.5 to 18.5. After the pups were reared to adult, we analyzed their GABAergic system in the PFC using immunohistological, biochemical, and behavioral analyses in adulthood. The prenatal PCP treatment decreased the density of parvalbumin-positive cells and reduced the expression level of glutamic acid decarboxylase 67 (GAD67) and GABA content of the PFC in adults. Additionally, prenatal PCP treatment induced behavioral deficits in adult mice, such as hypersensitivity to PCP and prepulse inhibition (PPI) deficits. These behavioral deficits were ameliorated by pretreatment with the GABAB receptor agonist baclofen. Furthermore, the density of c-FOS-positive cells was decreased after the PPI test in the PFC of mice treated with PCP prenatally, and this effect was ameliorated by pretreatment with baclofen. These findings suggest that prenatal treatment with PCP induced GABAergic dysfunction in the PFC, which caused behavioral deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 186 | Neurol. Res. 2016 Jan 38: 32-9 |
| PMID | 26883904 |
| Title | Stress alters asenapine-induced Fos expression in the Meynert's nucleus: response of adjacent hypocretin and melanin-concentrating hormone neurons in rat. |
| Abstract | Asenapine (ASE), an atypical antipsychotic drug used in the treatment of schizophrenia, induces FOS expression in forebrain. Effect of ASE on activity of basal nucleus of Meynert (NBM) cells, a part of the striatal-cortical circuits, was studied. We were also interested to reveal whether a chronic unpredictable variable mild stress (CMS) preconditioning might affect the ASE impact. Rats were divided into as follows: controls-vehicle, controls-ASE, stressed-vehicle and stressed-ASE groups. CMS included restrain, social isolation, crowding, swimming and cold applied for 21 days. On the 22nd day, rats were subcutaneously injected with ASE (0.3 mg/kg) or vehicle (saline 300 ?l/rat), 90 min prior euthanizing. After transcardial fixation, brains were cut into 30 ?m thick coronal sections. FOS protein presence, as indicator of cell activity, was detected by ABC immunohistochemistry. Hypocretin (Hcrt) and melanin-concentrating hormone (MCH) containing cells were visualized with fluorescent dyes. ASE induced significant increase in FOS expression in NBM in both controls and CMS preconditioned rats in comparison with the related vehicle-treated controls. CMS preconditioning, however, significantly lowered the FOS response to ASE in NBM. From Hrct and MCH cells, only Hcrt ones displayed FOS presence in response to ASE. This study demonstrates for the first time that ASE may target a special group of cells occupying NBM, which effect can be modulated by CMS preconditioning. This finding extends a view that ASE impact may extend beyond the classical forebrain target areas common for the action of all antipsychotics and might be helpful in the identification of sites and side effects of its therapeutic actions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |