| 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 |
| 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 |
| 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 |
| 4 | 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 |
| 5 | 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 |
| 6 | 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 |