| 1 | Mol. Psychiatry 2000 Mar 5: 203-7 |
|---|---|
| PMID | 10822350 |
| Title | Muscarinic1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia. |
| Abstract | Studies using tissue obtained at autopsy suggest that changes in cholinergic neurons could be important in the pathology of schizophrenia.1-4 We have previously reported a decrease in [3H]pirenzepine binding5 and [3H]AF-DX 384 binding6 to caudate-putamen (CP) from subjects who had schizophrenia. Under the conditions chosen, [3H]pirenzepine would predominately bind to muscarinic1 (M1) and muscarinic4 (M4) receptors,7whereas [3H]AF-DX 384 would mainly bind to muscarinic2 (M2) and M4 receptors.8 Given the relative concentrations of M1, M2 and M4 receptors in the human CP and the magnitude of the decreases in radioligand binding in schizophrenia, our results most likely reflected a change in the density of M1 and M2 receptors in the CP from the schizophrenic subjects. In situ hybridisation has now been used to determine levels of m1 and m2 mRNA in CP from 14 schizophrenic and 16 control subjects previously used for radioligand binding. m2 mRNA in the CP from the schizophrenic and control subjects was below the sensitivity of in situhybridisation. There was no difference in the levels of m1 mRNA in CP from schizophrenic and control subjects (mean +/- SEM: 103 +/- 16 vs106 +/- 17 fmol [35S]oligonucleotide probe g-1estimated tissue equivalents, P = 0.91). In conclusion, data from our radioligand binding studies show decreases in [3H]pirenzepine binding that are likely to reflect a decrease in the density of M1 receptors in CP from schizophrenic subjects. Our data in this study show the absence of a concomitant change in mRNA coding for that receptor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Mol. Psychiatry 2000 Mar 5: 203-7 |
| PMID | 10822350 |
| Title | Muscarinic1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia. |
| Abstract | Studies using tissue obtained at autopsy suggest that changes in cholinergic neurons could be important in the pathology of schizophrenia.1-4 We have previously reported a decrease in [3H]pirenzepine binding5 and [3H]AF-DX 384 binding6 to caudate-putamen (CP) from subjects who had schizophrenia. Under the conditions chosen, [3H]pirenzepine would predominately bind to muscarinic1 (M1) and muscarinic4 (M4) receptors,7whereas [3H]AF-DX 384 would mainly bind to muscarinic2 (M2) and M4 receptors.8 Given the relative concentrations of M1, M2 and M4 receptors in the human CP and the magnitude of the decreases in radioligand binding in schizophrenia, our results most likely reflected a change in the density of M1 and M2 receptors in the CP from the schizophrenic subjects. In situ hybridisation has now been used to determine levels of m1 and m2 mRNA in CP from 14 schizophrenic and 16 control subjects previously used for radioligand binding. m2 mRNA in the CP from the schizophrenic and control subjects was below the sensitivity of in situhybridisation. There was no difference in the levels of m1 mRNA in CP from schizophrenic and control subjects (mean +/- SEM: 103 +/- 16 vs106 +/- 17 fmol [35S]oligonucleotide probe g-1estimated tissue equivalents, P = 0.91). In conclusion, data from our radioligand binding studies show decreases in [3H]pirenzepine binding that are likely to reflect a decrease in the density of M1 receptors in CP from schizophrenic subjects. Our data in this study show the absence of a concomitant change in mRNA coding for that receptor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Neuroscience 2001 -1 103: 9-15 |
| PMID | 11311783 |
| Title | Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. |
| Abstract | A number of studies suggested that cannabis use can cause or exacerbate psychoses and may increase the risk of developing schizophrenia. These findings suggest that changes in the cannabinoid system of the brain may be involved in the pathology of schizophrenia. To determine whether changes in the cannabinoid system were present in the brains of subjects with schizophrenia, we used in situ radioligand binding and autoradiography to measure the binding of [3H]CP-55940 to the cannabinoid-1 receptor in the dorsolateral prefrontal cortex (Brodmann's area 9), caudate-putamen and areas of the temporal lobe from schizophrenic and control subjects, some of whom had ingested cannabis close to death. There was an increase in the density of [3H]CP-55940 binding to cannabinoid-1 receptors in the dorsolateral prefrontal cortex from subjects with schizophrenia (mean+/-S.E.M.: 142+/-9.9 vs 119+/-6.6fmol/mg estimated tissue equivalents; P<0.05) that was independent of recent cannabis ingestion. There was an increase in the density of cannabinoid-1 receptors in the caudate-putamen from subjects who had recently ingested cannabis (151+/-9.0 vs 123+/-7.2fmol/mg estimated tissue equivalents; P<0.05) that was independent of diagnoses. These data indicate that there are changes in cannabinoid-1 receptors in the dorsolateral prefrontal cortex that may prove to be associated with the pathology of schizophrenia. By contrast, changes in the density of cannabinoid-1 receptors may occur in the caudate-putamen in response to cannabis ingestion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Neuroscience 2001 -1 103: 9-15 |
| PMID | 11311783 |
| Title | Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. |
| Abstract | A number of studies suggested that cannabis use can cause or exacerbate psychoses and may increase the risk of developing schizophrenia. These findings suggest that changes in the cannabinoid system of the brain may be involved in the pathology of schizophrenia. To determine whether changes in the cannabinoid system were present in the brains of subjects with schizophrenia, we used in situ radioligand binding and autoradiography to measure the binding of [3H]CP-55940 to the cannabinoid-1 receptor in the dorsolateral prefrontal cortex (Brodmann's area 9), caudate-putamen and areas of the temporal lobe from schizophrenic and control subjects, some of whom had ingested cannabis close to death. There was an increase in the density of [3H]CP-55940 binding to cannabinoid-1 receptors in the dorsolateral prefrontal cortex from subjects with schizophrenia (mean+/-S.E.M.: 142+/-9.9 vs 119+/-6.6fmol/mg estimated tissue equivalents; P<0.05) that was independent of recent cannabis ingestion. There was an increase in the density of cannabinoid-1 receptors in the caudate-putamen from subjects who had recently ingested cannabis (151+/-9.0 vs 123+/-7.2fmol/mg estimated tissue equivalents; P<0.05) that was independent of diagnoses. These data indicate that there are changes in cannabinoid-1 receptors in the dorsolateral prefrontal cortex that may prove to be associated with the pathology of schizophrenia. By contrast, changes in the density of cannabinoid-1 receptors may occur in the caudate-putamen in response to cannabis ingestion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Acta Psychiatr Scand 2002 Mar 105: 173-8 |
| PMID | 11939970 |
| Title | Cannabis-induced psychosis: a cross-sectional comparison with acute schizophrenia. |
| Abstract | The existence of cannabis-induced psychosis (CP) remains controversial, partly because of methodological problems. We hypothesize that acute schizophrenia (AS) and CP can have distinct demographic, premorbid and clinical features. We compared 26 patients with CP to 35 with AS, after their cannabis-consumption status was confirmed by repeated urine screens. Patients with CP were assessed after at least 1 week but not more than 1 month of abstinence. Symptoms were evaluated with the Present State Examination (PSE). In group CP, male gender, expansive mood and ideation, derealization/depersonalization, visual hallucinations, and disturbances of sensorium were more frequent than in group AS. Premorbid schizoid personality traits were more frequently associated to AS and antisocial personality traits to CP. The continuous heavy use of cannabis can induce a psychotic disorder distinct from AS. These two clinical entities share some features but they differ in others. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Cleft Palate Craniofac. J. 2002 Jul 39: 392-6 |
| PMID | 12071787 |
| Title | Facial clefting and psychiatric diseases: a follow-up of the Danish 1936-1987 Facial Cleft cohort. |
| Abstract | This study assesses whether patients with facial cleft have an increased risk of psychiatric diseases. Through the Danish Facial Cleft Database, patients with facial cleft born between 1936 and 1987 in Denmark were identified, and the admission pattern for these patients with facial cleft was available for the period 1969 through 1993 through the Danish Psychiatric Central Registry. A total of 6,462 patients with facial cleft followed up for a total of 127,068 person-years. MAIN OUTCOME MEASURES Hospitalization for psychiatric diseases. The expected number of admissions for the cleft population was calculated by multiplication of the observed person-years with admission rates for Denmark stratified for sex, 1-year age group, and 1-year calendar period. A total of 284 patients with facial cleft (4.4%) were hospitalized for psychiatric diseases. The relative risk of hospitalization was 1.65 (95% confidence interval 1.3 to 2.0) for patients with isolated cleft palate (CP) and 1.15 (95% confidence interval 0.99 to 1.29) for patients with cleft lip +/- cleft palate (CL[P]). The overall risk estimates were above unity for both CP and CL(P) in all major diagnosis groups, neurosis and autism (for CL[P]) being the only exceptions. The excess risk was not accounted for by patients with known associated anomalies/syndromes. The risk of hospitalized mental disorders in general is increased in patients with CP but not to any substantial degree in patients with CL(P). Both groups had an increased risk of mental retardation and substance abuse, but the risk for schizophrenia or bipolar illness was not statistically significantly increased, compared with the background population. Further, our data provide no evidence that the psychosocial stressors associated with CL(P) and its treatment have any substantial impact on the risk for hospitalized mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Synapse 2003 Mar 47: 209-17 |
| PMID | 12494403 |
| Title | Effect of isolation rearing on pre- and post-synaptic serotonergic function in the rat dorsal hippocampus. |
| Abstract | Several behavioural, neurochemical, and structural alterations found in isolation-reared rats are similar to those in human schizophrenia. This study investigated changes in cholinergic and serotonergic function in the hippocampus following isolation rearing. Rats were reared in social isolation from weaning for 6 weeks before study and compared to group-reared rats. An in vitro electrophysiological study investigated the effect of isolation rearing on postsynaptic 5-HT(1A) function on CA1 hippocampal neurones activated with the muscarinic agonist carbachol and found no change in the sensitivity of these postsynaptic receptors between the groups. However, a change in presynaptic function was identified, as there was a significant reduction in the time taken for neuronal firing to recover to 50% of the original rate following 5-HT (10 microM) application, in isolation compared to group-reared rats. These data suggest a possible change in reuptake following isolation. Uptake studies using (3)[H]5-HT, however, found no change in the inhibition of uptake produced by either fluoxetine or paroxetine in isolation compared to group-reared rats. The selective 5-HT(1B) antagonist CP-294253 (1 microM), increased endogenous 5-HT release from hippocampal slices in vitro and this effect was greater (P < 0.001) in group compared to isolation-reared rats. These results indicate that the change in presynaptic 5-HT neuronal function was due to impaired autoreceptor responsiveness. Carbachol (1 microM) increased the firing rate of all neurones recorded but only a proportion of these showed a concentration-related increase. Isolation rearing increased the sensitivity of neurones, showing a concentration-related increase in firing in response to carbachol, but had no effect on the other neurones. In summary, the present study showed that isolation rearing alters presynaptic 5-HT(1B) but not postsynaptic 5-HT(1A) receptor activity in the hippocampus. Isolation rearing in the rat results in hippocampal dysfunction, including reduced serotonergic and enhanced muscarinic activity of some neurones. These effects may in part underlie the behavioural consequences of isolation relevant to human developmental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | J. Pharmacol. Sci. 2004 Dec 96: 376-81 |
| PMID | 15613777 |
| Title | New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia. |
| Abstract | Cannabis consumption may induce psychotic states in normal individuals, worsen psychotic symptoms of schizophrenic patients, and may facilitate precipitation of schizophrenia in vulnerable individuals. Recent studies provide additional biological and genetic evidence for the cannabinoid hypothesis of schizophrenia. Examinations using [3H]CP-55940 or [3H]SR141716A revealed that the density of CB1 receptors, a central type of cannabinoid receptor, is increased in subregions of the prefrontal cortex in schizophrenia. Anandamide, an endogenous cannabinoid, is also increased in the CSF in schizophrenia. A genetic study revealed that the CNR1 gene, which encodes CB1 receptors, is associated with schizophrenia, especially the hebephrenic type. Individuals with a 9-repeat allele of an AAT-repeat polymorphism of the gene may have a 2.3-fold higher susceptibility to schizophrenia. Recent findings consistently indicate that hyperactivity of the central cannabinoid system is involved in the pathogenesis of schizophrenia or the neural mechanisms of negative symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | J. Pharmacol. Sci. 2004 Dec 96: 376-81 |
| PMID | 15613777 |
| Title | New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia. |
| Abstract | Cannabis consumption may induce psychotic states in normal individuals, worsen psychotic symptoms of schizophrenic patients, and may facilitate precipitation of schizophrenia in vulnerable individuals. Recent studies provide additional biological and genetic evidence for the cannabinoid hypothesis of schizophrenia. Examinations using [3H]CP-55940 or [3H]SR141716A revealed that the density of CB1 receptors, a central type of cannabinoid receptor, is increased in subregions of the prefrontal cortex in schizophrenia. Anandamide, an endogenous cannabinoid, is also increased in the CSF in schizophrenia. A genetic study revealed that the CNR1 gene, which encodes CB1 receptors, is associated with schizophrenia, especially the hebephrenic type. Individuals with a 9-repeat allele of an AAT-repeat polymorphism of the gene may have a 2.3-fold higher susceptibility to schizophrenia. Recent findings consistently indicate that hyperactivity of the central cannabinoid system is involved in the pathogenesis of schizophrenia or the neural mechanisms of negative symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Naunyn Schmiedebergs Arch. Pharmacol. 2005 May 371: 428-33 |
| PMID | 15995876 |
| Title | Clozapine decreases [3H] CP 55940 binding to the cannabinoid 1 receptor in the rat nucleus accumbens. |
| Abstract | Antipsychotic drugs are effective in the treatment of cannabis-induced psychosis, but only clozapine appears effective in the treatment of comorbid schizophrenia and cannabis use. The unique effects of clozapine on cannabis use could, therefore, be due to an as yet unidentified interaction between clozapine and the endogenous cannabinoid system. To address this hypothesis, we used in situ radioligand binding and quantitative autoradiography with the selective cannabinoid CB1 receptor agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (side chain-2,3,4(N)-3H) ([3H]CP 55940) to measure the density of the CB1 receptor in frontal cortex, hippocampus, nucleus accumbens and striatum from rats treated with a variety of antipsychotic drugs. Clozapine significantly decreased [3H]CP 55940 binding in the nucleus accumbens compared with vehicle after 1 (35.0+/-14.0 vs. 71.2+/-8.5 fmol/mg estimated tissue equivalent (ete); P = 0.03) and 3 months (42.3+/-4.0 vs. 71.1+/-16.3 fmol/mg ete; P < 0.04) of treatment, an effect not observed with haloperidol, chlorpromazine or olanzapine. In rats treated with clozapine for 3 months and then left for 1 month without treatment, [3H]CP 55940 binding was not different in the nucleus accumbens (100.5+/-22.2 vs. 100.9+/-25.4 fmol/mg ete; P > 0.10). By contrast, there were significant increases in accumbal [3H]CP 55940 binding in rats treated with haloperidol (136.5+/-14.2 fmol/mg ete; P < 0.05), chlorpromazine (137.4+/-12.7 fmol/mg ete; P < 0.05) and olanzapine (144.7+/-10.1 fmol/mg ete; P < 0.01). These data indicate that in the nucleus accumbens clozapine differs from other antipsychotic drugs in its effects on [3H]CP 55940 binding. If these results can be extrapolated into humans, then this effect of clozapine on the CB1 receptor may be a mechanism that makes it uniquely effective in schizophrenia and comorbid cannabis use. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Exp Brain Res 2006 Jul 172: 556-60 |
| PMID | 16710682 |
| Title | Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. |
| Abstract | The posterior cingulate cortex (PCC) has recently been implicated in the pathophysiology of schizophrenia, through both animal and human studies. We have recently shown abnormal glutamate, GABA, and muscarinic receptor binding in the PCC in schizophrenia. In addition, there is evidence for an abnormal endogenous cannabinoid system in schizophrenia. The endogenous cannabinoid system, including CB1 receptors, is proposed to play a role in modulating neurotransmission via affecting the release of a variety of neurotransmitters, (e.g. GABA). In the present study, we used quantitative autoradiography to investigate the binding of [(3)H]CP-55940 to CB1 receptors in the PCC in schizophrenia subjects compared to controls. A significant 25% increase in CB1 binding was found in the superficial layers (layer I, II) of the PCC of schizophrenia subjects compared to controls, none of whom had recently used cannabis. There was no statistical difference in CB1 binding in the deeper layers (layers III-VI) between the two groups. There were no significant correlations between CB1 binding density and age, PMI, pH, brain weight, freezer storage time, or final recorded antipsychotic drug dose. These results show an increase in CB1 receptor density in the PCC in schizophrenia, and therefore provide support for a role of the endogenous cannabinoid system in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Nervenarzt 2006 Sep 77: 1096-100, 1102-4 |
| PMID | 16502008 |
| Title | [Cycloid psychoses as atypical manic-depressive disorders. Results of a family study]. |
| Abstract | Whereas a growing body of evidence suggests that cycloid psychoses have to be separated from schizophrenic psychoses, their relations to bipolar affective disorder are less clear. In a controlled family study, we recruited 46 patients with cycloid psychosis (CP), 33 with manic-depressive illness (MDI), and 27 controls. Three hundred fifty-six of 389 living first-degree relatives were personally examined by experienced psychiatrists blinded to the diagnosis of the index proband. The relatives of CP patients showed significantly lower morbidity risk of functional psychoses than relatives of patients with MDI in Kaplan-Meier life table calculation. The morbidity risk for functional psychoses in relatives of patients with CP did not differ significantly from that in relatives of controls. These results suggest that CP are etiologically different from bipolar affective psychoses and cannot be integrated into the spectrum of bipolar affective disorders. The findings provide further evidence for a nosological independence of CP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Schizophr. Res. 2006 Dec 88: 111-8 |
| PMID | 16956747 |
| Title | The selective effect of antipsychotics on the different dimensions of the experience of psychosis in schizophrenia spectrum disorders. |
| Abstract | While most standard symptom scales regard the 'psychotic' or 'positive' dimension of schizophrenia as a single factor, several lines of evidence suggest that psychosis itself is a multidimensional phenomenon. The foregoing literature suggested at least five distinct dimensions to psychosis; to test this, we developed, validated and applied an instrument to measure these dimensions and then applied it to examine the effect of antipsychotics on the different dimensions of the psychotic experience. The Dimensions of Psychosis Instrument (DIPI) was administered to 91 psychotic patients with schizophrenia spectrum disorders and a confirmatory factor analyses (CFA) was carried out to examine the five dimensions: cognitive preoccupation (CP) with the psychotic experience; emotional involvement (EM); behavioural impact (BI) of the experience; conviction (CO) in it; emotional; and external perspective (EP) about the experience. In a separate cohort of 17 prospectively treated patients, the impact of antipsychotics on these dimensions was assessed. BI showed the greatest improvement (32%) at 2 weeks, while CP and emotional improved somewhat less (22% and 14%, respectively). Improvement in CO was limited (6%) while EP showed no change. These results suggest that over the first few weeks of treatment, antipsychotics rapidly reduce the behavioural impact of the principal psychotic symptom and decrease cognitive and emotional preoccupation with it, without greatly altering the patients' conviction in or perspective about their psychotic experience. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Neurosci Bull 2007 Nov 23: 341-7 |
| PMID | 18064064 |
| Title | No changes in densities of cannabinoid receptors in the superior temporal gyrus in schizophrenia. |
| Abstract | In recent years, abnormal changes in the endocannabinoid system have been found in schizophrenia. The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In this study, we investigated the binding density of cannabinoid CB1 receptors in the STG of schizophrenia patients compared to control subjects. Quantitative autoradiography was used to investigate the binding densities of [(3)H]SR141716A (a selective antagonist) and [(3)H]CP-55940 (an agonist) to the CB1 receptors in the STG. Post-mortem brain tissue was obtained from the NSW Tissue Resource Centre (Australia). Contrasting to previous findings in the alterations of CB1 receptor densities in the prefrontal, anterior and posterior cingulate cortex of schizophrenia, which were suggested to be associated to impairment of cognition function, no significant difference was found between the schizophrenia and control cases in both [(3)H]SR141716A and [(3)H]CP-55940 binding. We suggest that CB1 receptors in the STG are not involved in the pathology of schizophrenia and the auditory hallucination symptom of this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Brain Res. 2007 Dec 1184: 260-9 |
| PMID | 17988657 |
| Title | The role of organic cation transporter-3 in methamphetamine disposition and its behavioral response in rats. |
| Abstract | Organic cation transporter-3 (OCT3) is expressed in several tissues including the brain. We have previously demonstrated that rats with behavioral sensitization to methamphetamine (METH) increased the brain penetration of METH with decreased expression of OCT3 in brain. Considering the earlier in vitro studies demonstrating that 1) OCT3 could transport dopamine (DA) and 2) the specific transport via OCT3 could be inhibited by METH, these results suggest that decreased OCT3 might decrease the efflux of METH and/or DA from brain, subsequently causing the development of behavioral sensitization. Thus, in the present study, behavioral task related to DA and pharmacokinetic experiment were performed using rats treated with antisense against OCT3 (OCT3-AS) since no specific ligands for OCT3 are still available. The continuous infusion of OCT3-AS into the third ventricle significantly decreased the expression of OCT3 in choroid plexus (CP) epithelial cells. Both METH-induced hyperlocomotion and METH-induced extracellular DA levels in nucleus accumbens and prefrontal cortex were significantly increased in OCT3-AS-treated rats. Moreover, the concentrations of METH were significantly increased in cerebrospinal fluid as well as extracellular areas at the nucleus accumbens in OCT3-AS-treated rats. These results suggested that decreased OCT3 elevated the concentration of METH and/or DA in brain, subsequently enhancing dopaminergic neuronal transmission and increasing METH-induced hyperlocomotion. In summary, OCT3 at the CP could regulate the effect of METH by controlling the levels of METH and/or DA in brain. Thus, these results suggest that OCT3 may be a new molecular target to treat METH-related disorders such as drug abuse and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Neuropharmacology 2007 Feb 52: 279-90 |
| PMID | 16949622 |
| Title | CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity. |
| Abstract | CP-809,101 is a potent, functionally selective 5-HT(2C) agonist that displays approximately 100% efficacy in vitro. The aim of the present studies was to assess the efficacy of a selective 5-HT(2C) agonist in animal models predictive of antipsychotic-like efficacy and side-effect liability. Similar to currently available antipsychotic drugs, CP-809,101 dose-dependently inhibited conditioned avoidance responding (CAR, ED(50)=4.8 mg/kg, sc). The efficacy of CP-809,101 in CAR was completely antagonized by the concurrent administration of the 5-HT(2C) receptor antagonist, SB-224,282. CP-809,101 antagonized both PCP- and d-amphetamine-induced hyperactivity with ED(50) values of 2.4 and 2.9 mg/kg (sc), respectively and also reversed an apomorphine induced-deficit in prepulse inhibition. At doses up to 56 mg/kg, CP-809,101 did not produce catalepsy. Thus, the present results demonstrate that the 5-HT(2C) agonist, CP-809,101, has a pharmacological profile similar to that of the atypical antipsychotics with low extrapyramidal symptom liability. CP-809,101 was inactive in two animal models of antidepressant-like activity, the forced swim test and learned helplessness. However, CP-809,101 was active in novel object recognition, an animal model of cognitive function. These data suggest that 5-HT(2C) agonists may be a novel approach in the treatment of psychosis as well as for the improvement of cognitive dysfunction associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Ann. Anat. 2008 -1 190: 324-8 |
| PMID | 18595676 |
| Title | Novel localization of tenascin-X in adult mouse leptomeninges and choroid plexus. |
| Abstract | Tenascin-X (Tn-X) belongs to the tenascin family of glycoproteins and is clearly associated with the human connective tissue disorder Ehlers-Danlos syndrome. Recently, human single nucleotide polymorphism analyses showed that Tn-X is associated with schizophrenia. Tn-X-related central nervous system (CNS) disorder has been reported in recent years. However, details of Tn-X localization are not clear in the adult cerebral cortex and its meninges. Using immunohistochemical techniques, we found novel localizations of Tn-X in the leptomeningeal trabecula (TB) of adult mice and in the connective tissue of the choroid plexus (CP) in the brains of mice. Subsequent immunohistochemical studies showed complementary localization of Tn-X in the leptomeninges and CP. Localization of tenascin-C was not detected in the leptomeningeal TB or in the connective tissue of the CP. These results might provide insight into the role of Tn-X in the pathogenesis of disorders in the CNS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Biol. Psychiatry 2008 Jun 63: 1075-83 |
| PMID | 18261715 |
| Title | Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia. |
| Abstract | Impaired auditory gating and abnormal neuronal synchrony are indicators of dysfunctional information processing in schizophrenia patients and possible underlying mechanisms of their impaired sensory and cognitive functions. Because cannabinoid receptors and endocannabinoids have been linked to psychiatric disorders, including schizophrenia, the aim of this study was to evaluate the effects of cannabinoid-1 (CB1) receptor activation on sensory gating and neuronal oscillations in rats. Auditory sensory gating has been recorded from the hippocampus and entorhinal cortex (EC) in anesthetized rats. Neuronal network oscillations were recorded from the hippocampus, medial septum, EC, and medial prefrontal cortex in anesthetized and freely moving rats. Effects of systemic administration of CB1 receptor agonist CP-55940 were evaluated on these parameters. CP-55940 significantly disrupted auditory gating both in the hippocampus and EC in anesthetized rats. Theta field potential oscillations were disrupted in the hippocampus and EC, with simultaneous interruption of theta-band oscillations of septal neurons. Administration of the CB1 receptor antagonist AM-251 reversed both the agonist-induced gating deficit and the diminished oscillations. In freely moving rats, CP-55940 significantly reduced theta and gamma power in the hippocampus, whereas in the EC, only gamma power was attenuated. However, novelty-induced theta and gamma activities were significantly diminished by CP-55940 in both the hippocampus and EC. Our data indicate that activation of CB1 receptors interferes with neuronal network oscillations and impairs sensory gating function in the limbic circuitry, further supporting the connection between cannabis abuse and increased susceptibility of developing schizophrenia spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Eur J Histochem 2009 Dec 53: e27 |
| PMID | 22073359 |
| Title | Identification of the novel localization of tenascinX in the monkey choroid plexus and comparison with the mouse. |
| Abstract | Tenascin-X (Tn-X) belongs to the tenascin family of glycoproteins and has been reported to be significantly associated with schizophrenia in a single nucleotide polymorphism analysis in humans. This finding indicates an important role of Tn-X in the central nervous system (CNS). However, details of Tn-X localization are not clear in the primate CNS. Using immunohistochemical techniques, we found novel localizations of Tn-X in the interstitial connective tissue and around blood vessels in the choroid plexus (CP) in macaque monkeys. To verify the reliability of Tn-X localization, we compared the Tn-X localization with the tenascin-C (Tn-C) localization in corresponding regions using neighbouring sections. Localization of Tn-C was not observed in CP. This result indicated consistently restricted localization of Tn-X in CP. Comparative investigations using mouse tissues showed equivalent results. Our observations provide possible insight into specific roles of Tn-X in CP for mammalian CNS function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Psychiatr Danub 2009 Sep 21: 283-9 |
| PMID | 19794343 |
| Title | Is there a cortical blood flow redistribution pattern related with perseverative error in schizophrenia? |
| Abstract | We studied relative cortical blood flow (relCBF) patterns associated to correct performance (CP) and perseverative error (PE) during Wisconsin Card Sorting Test (WCST) execution, in controls and patients with schizophrenia. relCBF (regional cortical blood flow (rCBF) / whole cortex blood flow) of 10 well defined cortical regions was measured in 18 patients with schizophrenia and 13 healthy controls by a Technetium - 99 - HMPAO - SPECT, at rest and while they performed WCST. Patients made significantly more PE than controls during WCST performance. In patients, we found a significant correlation between PE and relCBF in right occipital cortex. In controls, we found a significant correlation between CP and relCBF of several cortical regions during WCST execution: left orbitofrontal cortex and left global frontal cortex positively and parietal bilateral cortex negatively. PE was inversely correlated with relCBF in left temporal cortex. Successful WCST performance is associated to a high left frontal activity in controls but not in patients. The severity of PE during WCST performance is associated to a low left frontal-temporal activity in controls and to a high right parietal-occipital activity in schizophrenia. This may represent a cortical activity redistribution pattern related to perseveration in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | J Neural Transm (Vienna) 2009 Oct 116: 1335-47 |
| PMID | 19685198 |
| Title | Potential pathophysiological role of D-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain. |
| Abstract | D-Amino acid oxidase (DAO) is a peroxisomal flavoenzyme that catalyzes oxidative deamination of a wide range of D-amino acids. Among the possible substrates of DAO in vivo, D-serine is proposed to be a neuromodulator of the N-methyl-D-aspartate (NMDA) type glutamate receptor. The gene for DAO was reported to be associated with schizophrenia. Since DAO is expected to be one of the key enzymes in the regulation of NMDA neurotransmission, the modulation of the enzyme activity is expected to be therapeutical for neuronal disorders. In search of the pathophysiological role of DAO, we analyzed the distribution of DAO mRNA and protein in the rat and human brain. In rat, the distribution of DAO mRNA was newly detected in choroid plexus (CP) epithelial cells in addition to glial cells of pons, medulla oblongata, and especially Bergmann glia of cerebellum. Moreover, to investigate how DAO expression level is altered in schizophrenia, we performed immunohistochemistry in the human brain. In agreement with the results in the rat brain, the immunoreactivity for DAO was detected in glial cells of rhombencephalon and in CP. Furthermore, higher level of DAO expression was observed in schizophrenic CP epithelial cells than that in non-schizophrenic cases. These results suggest that an increase in DAO expression in parts of the brain is involved in aberrant D-amino acid metabolism. In particular, gene expression of DAO in CP suggests that DAO may regulate D-amino acid concentration by modulating the cerebrospinal fluid and may be regarded as a potential therapeutic target for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | J Neural Transm (Vienna) 2009 Oct 116: 1335-47 |
| PMID | 19685198 |
| Title | Potential pathophysiological role of D-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain. |
| Abstract | D-Amino acid oxidase (DAO) is a peroxisomal flavoenzyme that catalyzes oxidative deamination of a wide range of D-amino acids. Among the possible substrates of DAO in vivo, D-serine is proposed to be a neuromodulator of the N-methyl-D-aspartate (NMDA) type glutamate receptor. The gene for DAO was reported to be associated with schizophrenia. Since DAO is expected to be one of the key enzymes in the regulation of NMDA neurotransmission, the modulation of the enzyme activity is expected to be therapeutical for neuronal disorders. In search of the pathophysiological role of DAO, we analyzed the distribution of DAO mRNA and protein in the rat and human brain. In rat, the distribution of DAO mRNA was newly detected in choroid plexus (CP) epithelial cells in addition to glial cells of pons, medulla oblongata, and especially Bergmann glia of cerebellum. Moreover, to investigate how DAO expression level is altered in schizophrenia, we performed immunohistochemistry in the human brain. In agreement with the results in the rat brain, the immunoreactivity for DAO was detected in glial cells of rhombencephalon and in CP. Furthermore, higher level of DAO expression was observed in schizophrenic CP epithelial cells than that in non-schizophrenic cases. These results suggest that an increase in DAO expression in parts of the brain is involved in aberrant D-amino acid metabolism. In particular, gene expression of DAO in CP suggests that DAO may regulate D-amino acid concentration by modulating the cerebrospinal fluid and may be regarded as a potential therapeutic target for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Psychopharmacology (Berl.) 2009 Aug 205: 203-16 |
| PMID | 19421743 |
| Title | Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for "NMDA antagonist modelling" of schizophrenia. |
| Abstract | Little attention has been paid to the relative equivalence of behavioural effects of NMDA receptor antagonists in rodents, with different compounds often used interchangeably to "model" aspects of schizophrenia in preclinical studies. To further resolve such conjecture, the present study systematically compared eight different NMDA receptor antagonists: MK-801, PCP, ketamine, memantine, SDZ 220,581, Ro 25-6981, CP 101-606 and NVP-AAM077, in a series of variable interval (VI) schedules of reinforcement. Aspects of motivation as indexed in these tasks may well be impaired in schizophrenia and undoubtedly impact on the capacity to perform more complex, explicit tasks of cognition. An initial locomotor activity assessment demonstrated that all antagonists tested, except the NR2A-subunit preferring antagonist NVP-AAM077, induced hyperactivity, albeit of greatly differing magnitudes, qualities and temporal profiles. Three distinct patterns of antagonist effect were evident from the VI assays used: a uniform decrease in responding produced by (S)-(+)-ketamine, memantine and NVP-AAM077, a uniform increase in responding caused by the NR2B-subunit preferring antagonists Ro 25-6981 and CP 101-606, and variable bidirectional effects of PCP, SDZ 220,581 and MK-801. Despite nominally common mechanisms of action and often presumed biological equivalence, the NMDA antagonists tested produced very diverse effects on the expression of instrumental action. Other aspects of responding were left intact, including switching and matching behaviours, and the ability to respond to conditional stimuli. The implications of such findings with regard to animal modelling of schizophrenic psychotic symptoms are manifold. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Psychopharmacology (Berl.) 2009 Aug 205: 203-16 |
| PMID | 19421743 |
| Title | Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for "NMDA antagonist modelling" of schizophrenia. |
| Abstract | Little attention has been paid to the relative equivalence of behavioural effects of NMDA receptor antagonists in rodents, with different compounds often used interchangeably to "model" aspects of schizophrenia in preclinical studies. To further resolve such conjecture, the present study systematically compared eight different NMDA receptor antagonists: MK-801, PCP, ketamine, memantine, SDZ 220,581, Ro 25-6981, CP 101-606 and NVP-AAM077, in a series of variable interval (VI) schedules of reinforcement. Aspects of motivation as indexed in these tasks may well be impaired in schizophrenia and undoubtedly impact on the capacity to perform more complex, explicit tasks of cognition. An initial locomotor activity assessment demonstrated that all antagonists tested, except the NR2A-subunit preferring antagonist NVP-AAM077, induced hyperactivity, albeit of greatly differing magnitudes, qualities and temporal profiles. Three distinct patterns of antagonist effect were evident from the VI assays used: a uniform decrease in responding produced by (S)-(+)-ketamine, memantine and NVP-AAM077, a uniform increase in responding caused by the NR2B-subunit preferring antagonists Ro 25-6981 and CP 101-606, and variable bidirectional effects of PCP, SDZ 220,581 and MK-801. Despite nominally common mechanisms of action and often presumed biological equivalence, the NMDA antagonists tested produced very diverse effects on the expression of instrumental action. Other aspects of responding were left intact, including switching and matching behaviours, and the ability to respond to conditional stimuli. The implications of such findings with regard to animal modelling of schizophrenic psychotic symptoms are manifold. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Brain Res. 2009 May 1270: 121-30 |
| PMID | 19306847 |
| Title | Region-specific susceptibilities to cuprizone-induced lesions in the mouse forebrain: Implications for the pathophysiology of schizophrenia. |
| Abstract | Cuprizone (CPZ) is a neurotoxic agent acting as a copper chelator. In our recent study, C57BL/6 mice given dietary CPZ (0.2%) showed impairments in spatial working memory, social interaction, and prepulse inhibition. These abnormalities are reminiscent of certain schizophrenia symptoms and are not likely due to damage in the whole brain or in any single white matter tract/brain region. We hypothesized that white matter damage resulting from CPZ-treatment may be site-specific rather than universal. We examined the forebrains of C57BL/6 mice given the CPZ-containing diet and compared them with those of controls. We assessed CPZ-induced demyelination in main white matter tracts of the forebrain, evaluated myelin break down in the neuropil of the main olfactory bulb (MOB), cerebral cortex (CTX), caudate putamen (CP), hippocampus (HP), thalamus (TH), and hypothalamus (HY), and counted the number of myelin sheath forming oligodendrocytes (OLs) in CTX, CP, TH, and HY. Obvious demyelination was observed in the corpus callosum, external capsule, CP, and dorsal hippocampal commissure whereas other tracts seemed to be unaffected. The neuropil of CTX, HP and MOB showed myelin break down, which was mild in TH and HY. The number of OLs was decreased in all the above regions of CPZ-treated mice although the degree of OL loss was not consistent across regions. The data provide further support for white matter abnormalities contributing to schizophrenia-like behaviors in mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | J. Med. Chem. 2010 Feb 53: 1222-37 |
| PMID | 20043678 |
| Title | Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models. |
| Abstract | A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Psychopharmacology (Berl.) 2011 Sep 217: 255-69 |
| PMID | 21484239 |
| Title | A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory. |
| Abstract | N-methyl-D: -Aspartate receptor (NMDAR) antagonists such as ketamine induce cognitive symptoms in man similar to those of schizophrenia and therefore might be useful as models of the disease in animals. However, it is unclear which NMDAR antagonist(s) offer the best means to produce cognitive deficits in attention and working memory and to what extent those deficits can be measured selectively in rats. The present study systematically compared the effects of eight different NMDAR antagonists-MK-801, phencyclidine, (S)-(+)-ketamine, memantine, SDZ-220,581, Ro 25-6981, CP 101-606 and NVP-AAM077-in rats using standard tests of visual attention, the five-choice serial reaction time task (5CSRT), and working memory, the delayed matching to position task (DMTP). Drug-induced responses varied qualitatively and quantitatively in both a compound- and a task-dependent manner. Effects were generally confounded by concomitant motor and motivational disruption, although individual doses of phencyclidine for example appeared to impair selectively cognitive functions. Interestingly, GluN2B selective antagonists were unique in their effects; inducing potential performance benefit in the 5CSRT. Overall, the opportunity to induce a selective cognitive deficit in attention (5CSRT) or working memory (DMTP) in the rat is limited by both the NMDAR antagonist and the dose range used. The importance of a preclinical focus on ketamine, which is used more frequently in clinical settings, is limited by the extent to which cognitive effects can be both detected and quantified using this exposure regimen within these two operant assays. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Neuropsychopharmacology 2011 Jul 36: 1620-30 |
| PMID | 21471953 |
| Title | Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex. |
| Abstract | A number of studies suggest a dysregulation of the endogenous cannabinoid system in schizophrenia (SCZ). In the present study, we examined cannabinoid CB(1) receptor (CB(1)R) binding and mRNA expression in the dorsolateral prefrontal cortex (DLPFC) (Brodmann's area 46) of SCZ patients and controls, post-mortem. Receptor density was investigated using autoradiography with the CB(1)R ligand [(3)H] CP 55,940 and CB(1)R mRNA expression was measured using quantitative RT-PCR in a cohort of 16 patients with paranoid SCZ, 21 patients with non-paranoid SCZ and 37 controls matched for age, post-mortem interval and pH. All cases were obtained from the University of Sydney Tissue Resource Centre. Results were analyzed using one-way analysis of variance (ANOVA) and post hoc Bonferroni tests and with analysis of covariance (ANCOVA) to control for demographic factors that would potentially influence CB(1)R expression. There was a main effect of diagnosis on [(3)H] CP 55,940 binding quantified across all layers of the DLPFC (F(2,71) = 3.740, p = 0.029). Post hoc tests indicated that this main effect was due to patients with paranoid SCZ having 22% higher levels of CB(1)R binding compared with the control group. When ANCOVA was employed, this effect was strengthened (F(2,67) = 6.048, p = 0.004) with paranoid SCZ patients differing significantly from the control (p = 0.004) and from the non-paranoid group (p = 0.016). In contrast, no significant differences were observed in mRNA expression between the different disease subtypes and the control group. Our findings confirm the existence of a CB(1)R dysregulation in SCZ and underline the need for further investigation of the role of this receptor particularly in those diagnosed with paranoid SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Eur Arch Otorhinolaryngol 2011 Dec 268: 1713-9 |
| PMID | 21387190 |
| Title | Neuro-otological findings in psychiatric patients with nystagmus. |
| Abstract | To evaluate whether neuro-otological tests have clinical significance in psychiatric patients with nystagmus who have inner ear and/or brain dysfunction, we performed neuro-otological tests on 56 psychiatric patients with nystagmus (38 men, 18 women) (age range 40-97; mean age ± SD 61.6 ± 10.5 years). Patients were classified according to the underlying diseases: schizophrenia (25 cases), organic psychiatric disorders (14 cases), alcoholism (16 cases) and excited mental retardation (1 case). Caloric test results showed a normal response in 30 (75%) cases, right canal paresis (CP) in 4 (10%), left CP in 4 (10%) and bilateral CP in 2 (5%). Therefore, 10 (25%) cases had CP. The results of the eye tracking tests (ETT) were sorted into five categories: 4 (8.2%) cases smooth (normal), 8 (16.3%) slightly saccadic, 28 (57.1%) saccadic, 8 (16.3%) ataxic, and 1 (2%) no tracking ability. Therefore, 45 (91.8%) cases had abnormal ETT results. Pure tone audiometry showed normal hearing in 24 (47.1%) cases, right hearing loss (HL) in 3 (5.8%), left HL in 3 (5.8%) and bilateral HL in 21 (41.2%). Therefore, 27 (52.9%) cases had HL. The patients were classified as organic or functional groups. In ETT there was a significant difference between these two groups. These results indicate that neuro-otological tests with video-oculography are very important not only for neurological or neuro-otological patients with nystagmus, but also for psychiatric patients with nystagmus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Int. J. Neuropsychopharmacol. 2011 Feb 14: 29-42 |
| PMID | 20334724 |
| Title | Delta oscillation and short-term plasticity in the rat medial prefrontal cortex: modelling NMDA hypofunction of schizophrenia. |
| Abstract | Dysfunction of the prefrontal cortex (PFC) is considered to be an important factor contributing to a decrease in cognitive performance of schizophrenia patients. The medial PFC (mPFC) is innervated by the hippocampus/subiculum, and the subiculum-mPFC pathway is known to be involved in various cognitive processes. Glutamate-containing subicular axons innervate cortical pyramidal neurons and interneurons where AMPA and NMDA receptors are implicated in synaptic transmission. In our experiments, properties of subiculum-mPFC interactions were studied using pathway stimulation and local field potential (LFP) recordings of the mPFC in urethane-anaesthetized rats. Changes in paired-pulse facilitation (PPF) and LFP oscillations, effects of the NMDA receptor antagonist MK-801, and the AMPAkine LY451395 were evaluated. Effects of disruption of the thalamo-cortical loop with local microinjection of lidocaine into the mediodorsal thalamic nucleus (MD) were also studied. Our findings demonstrate that both systemic administration of MK-801 and local MD lidocaine microinjection produce similar changes in LFP oscillations and reduction in PPF. Specifically, it was observed that MK-801 (0.05 mg/kg i.v.) and intra-thalamic lidocaine changed regular, 2 Hz delta oscillation to a less regular 0.5-1.5 Hz delta rhythm. Concurrently, PPF in response to electrical stimulation of the subiculum was significantly attenuated. Administration of the AMPAkine LY451395 (0.01 mg/kg i.v.) reversed the MK-801- and lidocaine-induced changes, and was itself blocked by the AMPA receptor antagonist CP-465022. Analysis of our findings suggests a critical role of cortical interneurons in NMDA/AMPA receptor-mediated changes in thalamo-cortical oscillations and PPF, and contributes to our understanding of the NMDA hypofunction model of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Br. J. Pharmacol. 2012 Dec 167: 1480-91 |
| PMID | 22817643 |
| Title | First and second generation antipsychotics influence hippocampal gamma oscillations by interactions with 5-HT3 and D3 receptors. |
| Abstract | Disturbed cortical gamma band oscillations (30-80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease. Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs, respectively) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone, amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices. Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To determine which receptor is responsible for the alterations in gamma oscillations, the effects of the antipsychotics were plotted against their pK(i) values for 19 receptors and analysed for correlation. Our results indicated that 5-HT(3) receptors have an enhancing effect on gamma oscillations whereas dopamine D(3) receptors inhibit them. To test this prediction, m-chlorophenylbiguanide, PD 128907 and CP 809101, selective agonists at 5-HT(3) , D(3) and 5-HT(2C) receptors were applied and revealed that 5-HT(3) receptors indeed enhanced the gamma power whereas D(3) receptors reduced it. As predicted, 5-HT(2C) receptors had no effects on gamma oscillations. Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with 5-HT(3) and dopamine D(3) receptors. Moreover, a correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi-target drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Front Cell Neurosci 2012 -1 6: 31 |
| PMID | 22891052 |
| Title | Do genes and environment meet to regulate cerebrospinal fluid dynamics? Relevance for schizophrenia. |
| Abstract | schizophrenia is a neurodevelopment disorder in which the interplay of genes and environment contributes to disease onset and establishment. The most consistent pathological feature in schizophrenic patients is an enlargement of the brain ventricles. Yet, so far, no study has related this finding with dysfunction of the choroid plexus (CP), the epithelial cell monolayer located within the brain ventricles that is responsible for the production of most of the cerebrospinal fluid (CSF). Enlarged brain ventricles are already present at the time of disease onset (young adulthood) and, of notice, isolated mild ventriculomegaly detected in utero is associated with subsequent mild neurodevelopmental abnormalities similar to those observed in children at high risk of developing schizophrenia. Here we propose that altered CP/CSF dynamics during neurodevelopment may be considered a risk, causative and/or participating factor for development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Front Cell Neurosci 2012 -1 6: 31 |
| PMID | 22891052 |
| Title | Do genes and environment meet to regulate cerebrospinal fluid dynamics? Relevance for schizophrenia. |
| Abstract | schizophrenia is a neurodevelopment disorder in which the interplay of genes and environment contributes to disease onset and establishment. The most consistent pathological feature in schizophrenic patients is an enlargement of the brain ventricles. Yet, so far, no study has related this finding with dysfunction of the choroid plexus (CP), the epithelial cell monolayer located within the brain ventricles that is responsible for the production of most of the cerebrospinal fluid (CSF). Enlarged brain ventricles are already present at the time of disease onset (young adulthood) and, of notice, isolated mild ventriculomegaly detected in utero is associated with subsequent mild neurodevelopmental abnormalities similar to those observed in children at high risk of developing schizophrenia. Here we propose that altered CP/CSF dynamics during neurodevelopment may be considered a risk, causative and/or participating factor for development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | PLoS ONE 2012 -1 7: e39051 |
| PMID | 22815697 |
| Title | Adjusting brain dynamics in schizophrenia by means of perceptual and cognitive training. |
| Abstract | In a previous report we showed that cognitive training fostering auditory-verbal discrimination and working memory normalized magnetoencephalographic (MEG) M50 gating ratio in schizophrenia patients. The present analysis addressed whether training effects on M50 ratio and task performance are mediated by changes in brain oscillatory activity. Such evidence should improve understanding of the role of oscillatory activity in phenomena such as M50 ratio, the role of dysfunctional oscillatory activity in processing abnormalities in schizophrenia, and mechanisms of action of cognitive training. Time-locked and non-time-locked oscillatory activity was measured together with M50 ratio in a paired-click design before and after a 4-week training of 36 patients randomly assigned to specific cognitive exercises (CE) or standard (comparison) cognitive training (CP). Patient data were compared to those of 15 healthy controls who participated in two MEG measurements 4 weeks apart without training. Training led to more time-locked gamma-band response and more non-time-locked alpha-band desynchronization, moreso after CE than after CP. Only after CE, increased alpha desynchronization was associated with normalized M50 ratio and with improved verbal memory performance. Thus, both types of cognitive training normalized gamma activity, associated with improved stimulus encoding. More targeted training of auditory-verbal discrimination and memory additionally normalized alpha desynchronization, associated with improved elaborative processing. The latter presumably contributes to improved auditory gating and cognitive function. Results suggest that dysfunctional interplay of ocillatory activity that may contribute to auditory processing disruption in schizophrenia can be modified by targeted training. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Front Behav Neurosci 2013 -1 7: 149 |
| PMID | 24155701 |
| Title | An investigation into "two hit" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice. |
| Abstract | Reduced brain-derived neurotrophic factor (BDNF) signaling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET) and wild-type controls were chronically treated during weeks 6, 7, and 8 of life with the cannabinoid receptor agonist, CP55,940 (CP). After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI) was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [(3)H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus. These results show that BDNF deficiency and chronic young-adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male "two hit" mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [(3)H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential "two hit" neurodevelopmental mechanisms in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Neuropsychiatr Dis Treat 2013 -1 9: 1499-512 |
| PMID | 24109187 |
| Title | Role of nucleus accumbens glutamatergic plasticity in drug addiction. |
| Abstract | Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance's effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca(2+)-permeable AMPA receptors (CP-AMPARs) at the level of the NAc. Antagonism of the CP-AMPARs reduces cravings. It is necessary to pursue further exploration of the AMPA receptor subunit composition and variations at the level of the NAc for a better understanding of glutamatergic plastic changes. It is known that cocaine and morphine are able to induce changes in dendritic spine morphology by modifying actin cycling. These changes include an initial increase in spine head diameter and increases in AMPA receptor expression, followed by a second stage of spine head diameter retraction and reduction of the AMPA receptors' expression in spines. Besides glutamate and dopamine, other factors, like brain-derived neurotrophic factor (BDNF), can influence NAc activity and induce changes in dendritic spine density. BDNF also induces drug-related behaviors like self-administration and relapse. Neither apoptosis nor neurogenesis plays a relevant role in the neurobiological processes subjacent to cocaine addiction in adults (rodent or human). Different therapeutic drugs like N-acetylcysteine (NAC), modafinil, acamprosate, and topiramate have been tested in preclinical and/or clinical models for alleviating drug relapse. Moreover, these therapeutic drugs target the glutamatergic circuitry between the PFC and the NAc. NAC and acamprosate have shown inconsistent results in clinical trials. Modafinil and topiramate have shown some success, but more clinical trials are necessary. Based on the current review findings, it could be recommendable to explore therapeutic approaches that include synergism between different drugs and neurotransmitter systems. The discrepancy in the results of some therapeutic drugs between preclinical versus clinical trials for alleviating relapse or drug dependence could be linked to the scarce exploration of preclinical models that mimic polydrug abuse patterns, for example, cocaine plus alcohol. At the clinical level, the pattern of polydrug consumption is a phenomenon of considerable frequency. Finally, as a complement at the end, an updated summary is included about the role of glutamate in other neuropsychiatric disorders (for example, mood disorders, schizophrenia, and others). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Dev. Neurosci. 2013 -1 35: 384-95 |
| PMID | 24021607 |
| Title | Enhanced brain-derived neurotrophic factor signaling in the nucleus accumbens of juvenile rats. |
| Abstract | Brain-derived neurotrophic factor (BDNF) signaling through its receptor, tropomyosin receptor kinase B (TrkB), plays a critical role in neural plasticity and its dysregulation in striatum and prefrontal cortex (PFC) has been implicated in the etiology of mental health disorders such schizophrenia and drug addiction. In the present study, we characterized age-dependent differences in BDNF signaling and TrkB expression within the nucleus accumbens (NAc), caudate putamen (CP) and PFC in rats and determined the effects of administration of the dopamine agonist, SKF 83959, which activates the Gq-coupled dopamine receptors, the dopamine D5 receptor and the D1-D2 receptor heteromer. As proBDNF binds with high affinity to the p75 neurotrophin receptor (p75NTR), expression levels of these proteins were also assessed. The present findings showed that juvenile rats (aged 26-28 days) exhibited significantly elevated basal BDNF expression and activation of full-length TrkB (TrkBfull) in NAc compared to their adult counterparts, as evidenced by increased TrkBfull phosphorylation. These changes were concomitant with an increase in the relative expression of TrkBfull compared to the truncated isoform, TrkB.T1, in NAc and CP. Conversely, in PFC the basal expression of BDNF in juvenile rats was significantly lower than in adult rats with an elevated relative expression of TrkBfull. Acute administration of SKF 83959 to juvenile rats abolished the age-dependent differences in BDNF expression in NAc and PFC, and in the relative expression of TrkBfull in NAc and CP. Together these findings indicate that the expression and/or signaling of BDNF and TrkB in striatum and PFC of juvenile rats is fundamentally different from that of adult rats, a finding that may have implications in neuropsychiatric disorders that exhibit age-dependent susceptibility such as schizophrenia and drug addiction. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Psychiatry Res 2013 Dec 214: 365-73 |
| PMID | 24045051 |
| Title | Altered phospholipid metabolism in schizophrenia: a phosphorus 31 nuclear magnetic resonance spectroscopy study. |
| Abstract | Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naïve and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Psychiatry Res 2013 Dec 214: 365-73 |
| PMID | 24045051 |
| Title | Altered phospholipid metabolism in schizophrenia: a phosphorus 31 nuclear magnetic resonance spectroscopy study. |
| Abstract | Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naïve and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | J. Nutr. Biochem. 2013 Jul 24: 1349-58 |
| PMID | 23337348 |
| Title | DHA prevents altered 5-HT1A, 5-HT2A, CB1 and GABAA receptor binding densities in the brain of male rats fed a high-saturated-fat diet. |
| Abstract | Low levels of docosahexaenoic acid (DHA) have been linked to a number of mental illnesses such as memory loss, depression and schizophrenia. While supplementation of DHA is beneficial in improving memory and cognition, the influence of dietary fats on the neurotransmitters and receptors involved in cognitive function is still not known. The aim of this study was to investigate serotonin receptor (5-HT(1A) and 5-HT2A), cannabinoid receptor (CB1) and gamma-aminobutyric acid type A (GABA(A)) receptor binding densities in the brain of male rats fed a high-saturated-fat (HF) diet, as well as the effect of DHA supplementation on HF diet. Alterations of these receptors in the post-mortem rat brain were detected by [(3)H]-WAY-100635, [(3)H]-ketanserin, [(3)H]-CP-55,940 and [(3)H]-muscimol binding autoradiography, respectively. In the hippocampus, the 5-HT(1A), CB1 and GABA(A) receptor binding densities significantly increased in response to an HF diet, while in the hypothalamus, 5-HT(1A) and CB1 binding densities significantly increased in HF-fed rats. Importantly, DHA supplementation prevented the HF-induced increase of receptors binding density in the hippocampus and hypothalamus. Furthermore, DHA supplementation attenuated 5-HT2A receptor binding density in the caudate putamen, anterior cingulate cortex and medial mammillary nucleus, which was also increased in HF group. This study showed that an HF diet increased 5-HT(1A), 5-HT2A, CB1 and GABA(A) receptor binding densities in the brain regions involved in cognitive function and that dietary DHA can attenuate such alterations. These findings provide insight into the mechanism by which DHA supplementation ameliorates reduced cognitive function associated with an HF diet. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Synapse 2013 Mar 67: 145-59 |
| PMID | 23151877 |
| Title | Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT(2A)) receptor activity via ERK1/2 signaling. |
| Abstract | Recent behavioral studies suggest that nonselective agonists of cannabinoid receptors may regulate serotonin 2A (5-HT(2A)) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5-HT(2A) receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5-HT(2A) receptors. Here, we present experimental evidence that rats treated with a nonselective cannabinoid receptor agonist (CP 55,940, 50 µg/kg, 7 days) showed increases in 5-HT(2A) receptor protein levels, 5-HT(2A) receptor mRNA levels, and 5-HT(2A) receptor-mediated phospholipase C beta (PLC?) activity in prefrontal cortex (PFCx). Similar effects were found in neuronal cultured cells treated with CP 55,940 but these effects were prevented by selective CB2, but not selective CB1, receptor antagonists. CB2 receptors couple to the extracellular kinase (ERK) signaling pathway by G?(i/o) class of G-proteins. Noteworthy, GP 1a (selective CB2 receptor agonist) produced a strong upregulation of 5-HT(2A) receptor mRNA and protein, an effect that was prevented by selective CB2 receptor antagonists and by an ERK1/2 inhibitor, PD 198306. In summary, our results identified a strong cannabinoid-induced upregulation of 5-HT(2A) receptor signaling in rat PFCx. Our cultured cell studies suggest that selective CB2 receptor agonists upregulate 5-HT(2A) receptor signaling by activation of the ERK1/2 signaling pathway. Activity of cortical 5-HT(2A) receptors has been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results may provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to the pathophysiology of some cognitive and mood disorders in humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Front Psychiatry 2014 -1 5: 96 |
| PMID | 25140157 |
| Title | NR2B Antagonist CP-101,606 Abolishes Pitch-Mediated Deviance Detection in Awake Rats. |
| Abstract | schizophrenia patients exhibit a decreased ability to detect change in their auditory environment as measured by auditory event-related potentials (ERP) such as mismatch negativity. This deficit has been linked to abnormal NMDA neurotransmission since, among other observations, non-selective channel blockers of NMDA reliably diminish automatic deviance detection in human subjects as well as in animal models. Recent molecular and functional evidence links NR2B receptor subtype to aberrant NMDA transmission in schizophrenia. However, it is unknown if NR2B receptors participate in pre-attentive deviance detection. We recorded ERP from the vertex of freely behaving rats in response to frequency mismatch protocols. We saw a robust increase in N1 response to deviants compared to standard as well as control stimuli indicating true deviance detection. Moreover, the increased negativity was highly sensitive to deviant probability. Next, we tested the effect of a non-selective NMDA channel blocker (ketamine, 30?mg/kg) and a highly selective NR2B antagonist, CP-101,606 (10 or 30?mg/kg) on deviance detection. Ketamine attenuated deviance mainly by increasing the amplitude of the standard ERP. Amplitude and/or latency of several ERP components were also markedly affected. In contrast, CP-101,606 robustly and dose-dependently inhibited the deviant's N1 amplitude, and as a consequence, completely abolished deviance detection. No other ERPs or components were affected. Thus, we report first evidence that NR2B receptors robustly participate in processes of automatic deviance detection in a rodent model. Lastly, our model demonstrates a path forward to test specific pharmacological hypotheses using translational endpoints relevant to aberrant sensory processing in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Neuropharmacology 2014 Nov 86: 174-80 |
| PMID | 25063581 |
| Title | Enhancing ketamine translational pharmacology via receptor occupancy normalization. |
| Abstract | Ketamine is used preclinically and clinically to study schizophrenia and depression. Accordingly, it is imperative to understand the temporal relationship between the central concentrations and N-methyl-d-aspartate receptor (NMDAR) interactions of both ketamine and norketamine, its primary active metabolite, across species to assess the translatability of animal models to humans and the back-translation of clinical observations to the preclinical realm. However, such an interspecies normalization of ketamine and norketamine exposures at different clinical and preclinical doses (and their different routes and regimens) is lacking. This work defines the NMDAR occupancy (RO) time course following single doses of ketamine in rats, nonhuman primates (nhp) and humans to allow direct interspecies comparisons of specific ketamine-mediated pharmacodynamics via RO normalization. Total plasma concentration (CP)-time profiles of ketamine and norketamine were generated from rats and nhp following a single, memory-impairing dose of ketamine; neuropharmacokinetics were determined in rats. [(3)H]MK-801-displacement studies in rats determined estimated mean (95% confidence interval) unbound plasma concentrations (CP,u) for ketamine and norketamine producing 50% RO (IC50) of 1420 (990, 2140) nM and 9110 (5870, 13700) nM, respectively. Together, these datasets transformed CP,u-time data to predicted RO (ROpred)-time profiles for rats, nhp and humans at behaviorally relevant ketamine doses. Subsequently, this approach helped determine an infusion paradigm in rats producing a ROpred-time profile mirroring that for a clinically antidepressant infusion. The described indication-independent methodology allows normalization to RO at any time following any ketamine dose (regardless of route or regimen) in any species by simply quantifying the CP of ketamine and norketamine. Matching temporal RO relationships in animals and humans should allow direct comparisons of specific ketamine-dependent NMDAR-based pharmacodynamics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | BMC Psychiatry 2014 -1 14: 103 |
| PMID | 24708857 |
| Title | Study protocol: safety correction of high dose antipsychotic polypharmacy in Japan. |
| Abstract | In Japan, combination therapy with high doses of antipsychotic drugs is common, but as a consequence, many patients with schizophrenia report extrapyramidal and autonomic nervous system side effects. To resolve this, we proposed a method of safety correction of high dose antipsychotic polypharmacy (the SCAP method), in which the initial total dose of all antipsychotic drugs is calculated and converted to a chlorpromazine equivalent (expressed as milligrams of chlorpromazine, mg CP). The doses of low-potency antipsychotic drugs are then reduced by ? 25 mg CP/week, and the doses of high-potency antipsychotics are decreased at a rate of ? 50 mg CP/week. Although a randomized, case-controlled comparative study has demonstrated the safety of this method, the number of participants was relatively small and its results required further validation. In this study of the SCAP method, we aimed to substantially increase the number of participants. The participants were in- or outpatients treated with two or more antipsychotics at doses of 500-1,500 mg CP/day. Consenting participants were randomized into control and dose reduction groups. In the control group, patients continued with their normal regimen for 3 months without a dose change before undergoing the SCAP protocol. The dose reduction group followed the SCAP strategy over 3-6 months with a subsequent 3-month follow-up period. Outcome measures were measured at baseline and then at 3-month intervals, and included clinical symptoms measured on the Manchester scale, the extent of extrapyramidal and autonomic side effects, and quality of life using the Euro QOL scale. We also measured blood drug concentrations and drug efficacy-associated biochemical parameters. The Brief Assessment of Cognition in schizophrenia, Japanese version, was also undertaken in centers where it was available. The safety and efficacy of the SCAP method required further validation in a large randomized trial. The design of this study aimed to address some of the limitations of the previous case-controlled study, to build a more robust evidence base to assist clinicians in their efforts to reduce potentially harmful polypharmacy in this vulnerable group of patients. UMIN Clinical Trials Registry 000004511. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Psychiatry Res 2014 Mar 215: 579-85 |
| PMID | 24495574 |
| Title | Environmental factors during adolescence associated with later development of psychotic disorders - a nested case-control study. |
| Abstract | Etiologies of psychotic disorders (schizophrenia and bipolar disorder) are conceptualized as interplay between genetic and environmental factors. The adolescent period is characterized by changes in social roles and expectations that may interact with biological changes or psychosocial stressors. Few studies focus on the adolescents' own reports of perceived risk factors. To assess differences at age 16 between persons who later develop psychotic disorders ("Confirmed Psychosis", CP) and their class-mates ("Population Controls", PC) we collected information on: (1) Social support factors (size of social network and expectancies of social support from friends), (2) Cognitive functioning (concentrating in the classroom, actual grades and expectancies of own academic achievements) and (3) Problems and stressors in families (illness or loss of work for parents), and in relationship with others (exposure to bullying, violence or sexual violation). Self-reported data from students at 15-16 years of age were linked to the case-registers from the "Thematically Organized Psychosis (TOP) Study". The CP group reported more economic problems in their families, smaller social network and lower academic expectation than the PC group. The results support the notion that long-term socioeconomic stressors in adolescence may serve as risk factors for the development of psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Neuropsychopharmacology 2014 Jun 39: 1578-93 |
| PMID | 24442096 |
| Title | Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100. |
| Abstract | Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Brain Behav. Immun. 2015 Nov 50: 1-13 |
| PMID | 26116435 |
| Title | Therapeutic implications of the choroid plexus-cerebrospinal fluid interface in neuropsychiatric disorders. |
| Abstract | The choroid plexus (CP) comprises an epithelial monolayer that forms an important physical, enzymatic and immunologic barrier, called the blood-cerebrospinal fluid barrier (BCSFB). It is a highly vascularized organ located in the brain ventricles that is key in maintaining brain homeostasis as it produces cerebrospinal fluid (CSF) and has other important secretory functions. Furthermore, the CP-CSF interface plays a putative role in neurogenesis and has been implicated in neuropsychiatric diseases such as the neurodevelopmental disorders schizophrenia and autism. A role for this CNS border was also implicated in sleep disturbances and chronic and/or severe stress, which are risk factors for the development of neuropsychiatric conditions. Understanding the mechanisms by which disturbance of the homeostasis at the CP-CSF interface is involved in these different chronic low-grade inflammatory diseases can give new insights into therapeutic strategies. Hence, this review discusses the different roles that have been suggested so far for the CP in these neuropsychiatric disorders, with special attention to potential therapeutic applications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | Psychiatry Res 2015 Jan 225: 70-8 |
| PMID | 25454115 |
| Title | Assessing motivation orientations in schizophrenia: Scale development and validation. |
| Abstract | Motivation deficits are common in several disorders including schizophrenia, and are an important factor in both functioning and treatment adherence. Self-Determination Theory (SDT), a leading macro-theory of motivation, has contributed a number of insights into how motivation is impaired in schizophrenia. Nonetheless, self-report measures of motivation appropriate for people with severe mental illness (including those that emphasize SDT) are generally lacking in the literature. To fill this gap, we adapted and abbreviated the well-validated General Causality Orientation Scale for use with people with schizophrenia and with other severe mental disorders (GCOS-clinical populations; GCOS-CP). In Study 1, we tested the similarity of our measure to the existing GCOS (using a college sample) and then validated this new measure in a schizophrenia and healthy control sample (Study 2). Results from Study 1 (N=360) indicated that the GCOS-CP was psychometrically similar to the original GCOS and provided good convergent and discriminant validity. In Study 2, the GCOS-CP was given to individuals with (N=44) and without schizophrenia (N=42). In line with both laboratory-based and observer-based research, people with schizophrenia showed lower motivational autonomy and higher impersonal/amotivated orientations. Additional applications of the GCOS-CP are discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Psychopharmacology (Berl.) 2015 Nov 232: 3991-4003 |
| PMID | 26184010 |
| Title | Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation. |
| Abstract | N-methyl-D-aspartate (NMDA) receptors play crucial roles in learning and memory, but the role of each NMDA receptor subtype in a specific cognitive process is unclear. Non-selective blockers of NMDA receptor are used to model the cognitive impairment in schizophrenia and Alzheimer's disease. Counter-intuitively selective NR2A and 2B NMDA receptor antagonists are thought to have pro-cognitive properties. These seemingly contrasting findings might in part be the result of different compounds and behavioral measures used across studies. We compared the effect of NVP-AAM077 (NR2A antagonist), CP 101-606 (NR2B antagonist), and MK-801 (non-selective antagonist) in a series of touch screen tasks that can be used to measure spatial cognition and cognitive flexibility. NVP-AAM077, CP 101-606, and MK-801 were administered prior to testing, in adult male Lister-hooded rats trained in tasks of location discrimination, paired associate learning (PAL), and trial unique non-match to location (TUNL). Results showed that MK-801 impaired performance on all the tasks. In contrast, CP 101-606 only impaired reversal learning in location discrimination and had minimal effect on working memory in TUNL and caused a modest improvement in accuracy in PAL and acquisition of a spatial discrimination. NVP-AAM077 had little effect on performance across tasks, although these data allude to a potential enhancement of acquisition of a spatial location and impairments in spatial reversal learning in a separation-dependent manner. These data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Biol. Psychiatry 2015 Jun 77: 969-78 |
| PMID | 25542305 |
| Title | Nitric oxide synthase 1 adaptor protein, a protein implicated in schizophrenia, controls radial migration of cortical neurons. |
| Abstract | Where a neuron is positioned in the brain during development determines neuronal circuitry and information processing needed for normal brain function. When aberrations in this process occur, cognitive disorders may result. Patients diagnosed with schizophrenia have been reported to show altered neuronal connectivity and heterotopias. To elucidate pathways by which this process occurs and become aberrant, we have chosen to study the long isoform of nitric oxide synthase 1 adaptor protein (NOS1AP), a protein encoded by a susceptibility gene for schizophrenia. To determine whether NOS1AP plays a role in cortical patterning, we knocked down or co-overexpressed NOS1AP and a green fluorescent protein or red fluorescent protein (TagRFP) reporter in neuronal progenitor cells of the embryonic rat neocortex using in utero electroporation. We analyzed sections of cortex (ventricular zone, intermediate zone, and cortical plate [CP]) containing green fluorescent protein or red fluorescent protein TagRFP positive cells and counted the percentage of positive cells that migrated to each region from at least three rats for each condition. NOS1AP overexpression disrupts neuronal migration, resulting in increased cells in intermediate zone and less cells in CP, and decreases dendritogenesis. Knockdown results in increased migration, with more cells reaching the CP. The phosphotyrosine binding region, but not the PDZ-binding motif, is necessary for NOS1AP function. Amino acids 181 to 307, which are sufficient for NOS1AP-mediated decreases in dendrite number, have no effect on migration. Our studies show for the first time a critical role for the schizophrenia-associated gene NOS1AP in cortical patterning, which may contribute to underlying pathophysiology seen in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Neuropsychopharmacology 2015 Mar 40: 839-48 |
| PMID | 25241801 |
| Title | Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder. |
| Abstract | Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic- and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | PLoS ONE 2016 -1 11: e0156261 |
| PMID | 27223812 |
| Title | Psychiatric Diagnoses in Individuals with Non-Syndromic Oral Clefts: A Danish Population-Based Cohort Study. |
| Abstract | The aim of this study was to investigate the risk of psychiatric diagnoses in individuals with non-syndromic oral clefts (OC) compared with individuals without OC, including ages from 1 to 76 years. Linking four Danish nationwide registers, we investigated the risk of psychiatric diagnoses at Danish psychiatric hospitals during the period 1969-2012 for individuals born with non-syndromic OC in Denmark 1936-2009 compared with a cohort of 10 individuals without OC per individual with OC, matched by sex and birth year. The sample included 8,568 individuals with OC, observed for 247,821 person-years, and 85,653 individuals without OC followed for 2,501,129 person-years. A total of 953 (11.1%) of the individuals with OC (9.6% for cleft lip (CL), 10.8% for cleft lip and palate (CLP) and 13.1% for cleft palate (CP)) and 8,117 (9.5%) in the comparison group had at least one psychiatric diagnosis. Cox proportional hazard regression model revealed that individuals with OC had significantly higher risk of a psychiatric diagnosis (hazard ratio (HR) = 1.19, 95% CI: 1.12-1.28). When examining cleft type, no difference was found for CL (HR = 1.03, 95% CI: 0.90-1.17), but CLP was associated with a small increased risk (HR = 1.13, 95% CI: 1.01-1.26), whereas individuals with CP had the largest increased risk (HR = 1.45, 95% CI: 1.30-1.62). The largest differences were found in schizophrenia-like disorders, mental retardation and pervasive developmental disorders, but we found no increased risk of mood disorders and anxiety-related disorders. Individuals with non-syndromic OC had significantly higher risk of psychiatric diagnoses compared with individuals without OC. However, the elevated risk was observed for individuals with CLP and CP but not for individuals with CL and the absolute risk increase was modest. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Int J Pharm 2016 Apr 503: 8-15 |
| PMID | 26899975 |
| Title | Sustained release of risperidone from biodegradable microspheres prepared by in-situ suspension-evaporation process. |
| Abstract | Risperidone-loaded poly (d,l-lactide-co-glycolide) (PLGA) microspheres were prepared with a suspension-evaporation process with an aqueous suspension containing an in situ-formed aluminum hydroxide inorganic gel (SEP-AL process) and evaluated for encapsulation efficiency, particle size, surface morphology, glass transition temperature, in vitro drug release profile, and in vivo behavior. The SEP-AL microspheres were compared with conventional oil-in-water (O/W) emulsion solvent evaporation method using polyvinylalcohol (PVA) as an emulsifier (CP-PVA process). The microspheres were spherical in shape. DSC measurements showed that risperidone crystallinity was greatly reduced due to the homogeneous distribution of risperidone in PLGA microspheres. In vitro drug release profile from the microspheres showed a sigmoidal pattern of negligible initial burst up to 24h and minimal release (time-lag) for 7days. After the lag phase, slow release took a place up to 25days and then rapid release occurred sharply for 1 week. In vivo rat pharmacokinetic profile from the microspheres showed very low blood concentration level at the initial phase (up to 24h) followed by the latent phase up to 21days. At the 3rd week, main phase started and the blood concentration of the drug increased up to the 5th week, and then gradually decreased. The risperidone-loaded PLGA microspheres produced by SEP-AL process showed excellent controlled release characteristics for the effective treatment of schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |