Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently developed antipsychotic drugs ameliorating the negative symptoms of schizophrenia act not only on dopamine D2 receptors but also on serotonin 2A (5-HT2A) and 1A (5-HT1A) receptors in specific regions of the cerebral cortex. Since it is not yet known whether serotonin 5-HT1A and 5-HT2A receptors coexist in the same population of neurons in the cortex, the present study investigated their colocalization in the rat medial prefrontal (MPC) and entorhinal (EC) cortices. Using antibodies that recognize epitopes specific to the serotonin 5-HT2A or 5-HT1A receptors, studies employing confocal microscopy have shown that in the MPC 5-HT2A receptors are preferentially, if not exclusively, present on the pyramidal neurons and that 5-HT1A-immunopositive material is present in the axonal hillocks and, to lower extend, in cytoplasm of presumably pyramidal cell bodies. With the regard of labeling of active receptors (i.e. present in shafts and axonal hillocks) we found that about 38% of neurons positive for the presence of serotonin 5-HT2A receptors, are also positive for serotonin 5-HT1A receptors in the MPC. In the EC, only 22% of serotonin 5-HT2A-positive neurons were positive for serotonin 5-HT1A receptor-immunoreactivity. In the respect of cytoplasmatic serotonin 5-HT1A receptor-immunoreactivity (possibly inactive receptors), 65% and 73% of serotonin 5-HT2A receptor-positive neurons were colocalized with serotonin 5-HT1A receptors in the MPC and EC, respectively. Data obtained on serotonin 5-HT2A and 5-HT1A receptor localization provide anatomical grounds for at least three distinct populations of pyramidal neurons, one governed only by 5-HT2A, one only by 5-HT1A and one by both types of serotonin receptors.
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PMID:A search for colocalization of serotonin 5-HT2A and 5-HT1A receptors in the rat medial prefrontal and entorhinal cortices--immunohistochemical studies. 1862 42

Several novel antipsychotics activate serotonin 5-HT1A receptors as well as antagonising dopamine D2/3 receptors. Such a pharmacological profile is associated with a lowered liability to produce extrapyramidal side effects and enhanced efficacy in treating negative and cognitive symptoms of schizophrenia. However, 5-HT1A receptor agonists increase plasma corticosterone and many antipsychotics disturb the regulation of glucose. Here, we compared the influence on plasma glucose and corticosterone of acute treatments with 'new generation' antipsychotics which target dopamine D2/3 receptors and 5-HT1A receptors, with that of atypical antipsychotics, and with haloperidol. Olanzapine and clozapine, antipsychotics that are known to produce weight gain and diabetes in humans, both at 10 mg/kg p.o., substantially increased plasma glucose (from 0.8 to 1.7 g/l) at 1 h after administration, an effect that returned to control levels after 4 h. In comparison, F15063 (40 mg/kg p.o.) was without effect at any time point. Olanzapine and clozapine dose-dependently increased plasma glucose concentrations as did SLV313 and SSR181507. Haloperidol and risperidone had modest effects whereas aripiprazole, ziprasidone and bifeprunox, antipsychotics that are not associated with metabolic dysfunction in humans, and F15063 had little or no influence on plasma glucose. The same general pattern of response was found for plasma corticosterone levels. The present data provide the first comparative study of conventional, atypical and 'new generation' antipsychotics on glucose and corticosterone levels in rats. A variety of mechanisms likely underlie the hyperglycemia and corticosterone release observed with clozapine and olanzapine, whilst the balance of dopamine D2/3/5-HT1A interaction may contribute to the less favourable impact of SLV313 and SSR181507 compared with that of bifeprunox and F15063.
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PMID:The antipsychotics clozapine and olanzapine increase plasma glucose and corticosterone levels in rats: comparison with aripiprazole, ziprasidone, bifeprunox and F15063. 1864 Jan 11

Panic disorder (PD) and social anxiety disorder (SAD) are moderately heritable anxiety disorders. We analyzed five genes, derived from pharmacological or translational mouse models, in a new case-control study of PD and SAD in European Americans: (1) the serotonin transporter (SLC6A4), (2) the serotonin receptor 1A, (3) catechol-O-methyltransferase, (4) a regulator of g-protein signaling and (5) the gastrin-releasing peptide receptor. Cases were interviewed using the schedule for affective disorders and schizophrenia and were required to have a probable or definite lifetime diagnosis of PD (N=179), SAD (161) or both (140), with first onset by age 31 and a family history of anxiety. Final diagnoses were determined using the best estimate procedure, blind to genotyping data. Controls were obtained from the National Institute of Mental Health Human Genetics Initiative; only subjects above 25 years of age who screened negative for all psychiatric symptoms were included (N=470). A total of 45 single nucleotide polymorphisms were successfully genotyped over the five selected genes using Applied Biosystems SNPlex protocol. SLC6A4 provided strong and consistent evidence of association with the PD and PD+SAD groups, with the most significant association in both groups being at rs140701 (chi(2)=10.72, P=0.001 with PD and chi(2)=8.59, P=0.003 in the PD+SAD group). This association remained significant after multiple test correction. Those carrying at least one copy of the haplotype A-A-G constructed from rs3794808, rs140701 and rs4583306 have 1.7 times the odds of PD than those without the haplotype (95% confidence interval: 1.2-2.3). The SAD only group did not provide evidence of association, suggesting a PD-driven association. The findings remained after adjustment for age and sex, and there was no evidence that the association was due to population stratification. The promoter region of the gene, 5-HTTLPR, did not provide any evidence of association, regardless of whether analyzed as a triallelic or biallelic locus, nor did any of the other four candidate genes tested. Our findings suggest that the serotonin transporter gene may play a role in PD; however, the findings require replication. Future studies should attend to the entire genetic region rather than the promoter.
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PMID:Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). 1866 69

This study aimed to explore strain and species differences in the involvement of 5-HT1A receptors in the action of antipsychotic drugs, using prepulse inhibition (PPI), a model of sensory processing which is deficient in schizophrenia patients. We used automated startle boxes to compare the effect of the 5-HT1A receptor agonist, (+/-)-8-hydroxy-dipropyl-amino-tetralin (8-OH-DPAT), on PPI in three mouse strains. Balb/c mice were then pretreated with antipsychotics, treated with 8-OH-DPAT or saline, and tested for PPI. 8-OH-DPAT treatment dose dependently increased PPI in Balb/c mice, but had less effect in 129Sv and C57Bl/6 mice. In Balb/c mice, the effect of 8-OH-DPAT was blocked by the typical antipsychotic and dopamine D2 receptor antagonist, haloperidol and the third generation antipsychotic, aripiprazole, which has activity at both 5-HT1A and dopamine D2 receptors. The atypical antipsychotics, clozapine, olanzapine and risperidone, had lesser effects. Similar to our earlier studies in rats, the present PPI results suggest that 5-HT1A receptors are involved in the action of some antipsychotic drugs in mice. Despite strain and species differences in the magnitude and direction of the effect of 8-OH-DPAT, downstream dopamine D2 receptor activation seems to be an important mediator. These comparative results allow a theoretical framework of receptor interactions, which may guide further studies on the involvement of 5-HT1A receptors in schizophrenia.
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PMID:Role of serotonin-1A receptors in the action of antipsychotic drugs: comparison of prepulse inhibition studies in mice and rats and relevance for human pharmacology. 1869 Jan 9

Metachromatic leukodystrophy (MLD) is a metabolic disease that has recently been investigated as a model for the study of psychosis. We report on two sisters with adult-type MLD who developed psychiatric symptomatology, but differed in their expression of psychotic and depressive symptoms. Association studies have indicated that polymorphisms in genes encoding the serotonin and dopamine transporters and receptors are related to the symptomatology of schizophrenia and/or depression; hence both sisters were genotyped for some of these candidate genes. The sisters shared dopamine receptor D(2) (DRD(2)) c.1047GG (p.311Ser/Ser) and c.-141Cins/ins polymorphisms, which are significantly associated with schizophrenia, but differed in the serotonin transporter gene-linked polymorphic region and serotonin receptor 1A (5-HT(1A)) c.-1019C to G polymorphisms, which may have increased the elder sister's susceptibility to depressive symptoms. Much bigger samples would be needed to gain enough statistical power to develop any hypotheses. This is the first report on genotyping MLD patients for candidate genes for psychiatric disorders, although MLD has been proposed as a model for schizophrenia.
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PMID:Polymorphisms in genes encoding the serotonin and dopamine pathways in two sisters with metachromatic leukodystrophy. 1883 10

The serotonin (5-HT) 1A receptor has been found to be dysregulated in prefrontal cortex and other brain regions in schizophrenia, and 5-HT1A receptor levels in the amygdala have been related to negative schizophrenia symptoms. We have assessed the impact of the functional C-1019G variant of the 5-HT1A receptor on the response to risperidone or haloperidol in a prospective, randomized, double-blind study. Patients were treated for 4 weeks and negative symptoms assessed weekly. The variant influenced the response to risperidone: improvement of negative symptoms by 4.38 points for carriers of the C allele, compared with the GG genotype (1.22 points, P=0.046). In a second independent study of 130 schizophrenia patients treated with atypical antipsychotics, this effect was confirmed (P=0.003). The functional variant of the 5-HT1A receptor thus influences the response of schizophrenia patients to atypical antipsychotics and may be useful in the future to predict the pharmacogenetics of negative symptoms.
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PMID:Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia. 1884 90

Several lines of evidence suggest an important role of the S100B protein and its coding gene in different neuropathological and psychiatric disorders like dementia, bipolar affective disorders and schizophrenia. To clarify whether a direct link exists between gene and gene product, that is, whether S100B variants directly modulate S100B serum concentration, 196 healthy individuals were assessed for S100B serum concentrations and genotyped for five potentially functional S100B SNPs. Functional variants of the serotonergic genes 5-HT1A and 5-HTT possibly modulating S100B serum levels were also studied. Further, publicly available human postmortem gene expression data were re-analyzed to elucidate the impact of S100B, 5-HT1A and 5-HTT SNPs on frontal cortex S100B mRNA expression. Several S100B SNPs, particularly rs9722, and the S100B haplotype T-G-G-A (including rs2186358-rs11542311-rs2300403-rs9722) were associated with elevated S100B serum concentrations (Bonferroni corrected P < 0.05). Of these, rs11542311 was also associated with S100B mRNA expression directly (Bonferroni corrected P = 0.05) and within haplotype G-A-T-C (rs11542311-rs2839356-rs9984765-rs881827; P = 0.004), again with the G-allele increasing S100B expression. Our results suggest an important role of S100B SNPs on S100B serum concentrations and S100B mRNA expression. It hereby links recent evidence for both, the impact of S100B gene variation on various neurological or psychiatric disorders like dementia, bipolar affective disorders and schizophrenia and the strong relation between S100B serum levels and these disorders.
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PMID:Risk variants in the S100B gene predict elevated S100B serum concentrations in healthy individuals. 1933 Jul 75

Neuregulin 1 (Nrg1) has been widely recognized as a candidate gene for schizophrenia. This study therefore investigated mice heterozygous for a mutation in the transmembrane domain of this trophic factor (Nrg1+/- mice) in a number of behavioural test systems with relevance to schizophrenia, including psychotropic drug-induced locomotor hyperactivity and prepulse inhibition (PPI) of startle. Baseline locomotor activity in the open field or in photocell cages was slightly, but significantly enhanced in Nrg1+/- mice compared to wild-type littermate controls at age 12-16 wk, but not at age 6 months. The ability of amphetamine, phencyclidine (PCP) or MK-801 to induce locomotor hyperactivity was not significantly different between the genotypes. There was no difference in baseline PPI, startle or startle habituation and there was no difference in the effect of apomorphine, amphetamine or MK-801 on any of these parameters. Only treatment with the 5-HT1A receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) showed a differential effect between genotypes, with a disruption of PPI occurring in Nrg1+/- mice compared to no effect in wild-type controls. This treatment also induced a significant reduction of startle which could have influenced the result. The density of dopamine D2 receptors in the forebrain and of 5-HT1A receptors in the hippocampus and raphe nuclei was not different between Nrg1+/- mice and controls. These studies add to the knowledge about behavioural effects in this mouse model of impaired Nrg1 function and suggest that a number of the behavioural tests with relevance to schizophrenia are normal in these mice.
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PMID:Neuregulin 1 hypomorphic mutant mice: enhanced baseline locomotor activity but normal psychotropic drug-induced hyperlocomotion and prepulse inhibition regulation. 1940 Sep 83

It seems that the efficacy of aripiprazole for treating schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors. Aripiprazole has also received approval for the treatment of bipolar disorder as adjunctive therapy or monotherapy (manic or mixed episodes) as well as an augmentation therapy of major depressive disorder (MDD) by the US FDA. The overall safety and tolerability of aripiprazole is favorable compared to other atypical antipsychotics across the approved indications. Aripiprazole showed a minimal propensity for clinically significant weight gain and metabolic disruption. However, extrapyramidal side effects, such as akathisia, are reported and may limit its clinical use in some cases, particularly in patients with bipolar disorder and MDD. This review focuses on the tolerability and safety of aripiprazole across a broad spectrum of psychiatric disorders while taking into consideration results from registrational studies as well as findings from studies in the naturalistic setting. In conclusion, whereas the comparative safety and tolerability of aripiprazole has not been systematically evaluated in comparator studies, tolerability and safety issues commonly associated with atypical antipsychotics such as weight gain and metabolic syndrome are less prominent with aripiprazole.
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PMID:A review of the safety and tolerability of aripiprazole. 1950 66

Olanzapine treatment has been associated with clinically meaningful weight increases, hypertriglyceridemia, insulin resistance, and diabetes mellitus. There are few options for olanzapine responders who fail other antipsychotic agents. Aripiprazole is a potent (high-affinity) partial agonist at D2 and 5-HT1A receptors and a potent antagonist at 5-HT2A receptor and is associated with less weight gain than olanzapine. We report the results of a 10-week placebo-controlled, double-blind crossover study that examined 15 mg/d aripiprazole's effects on weight, lipids, glucose metabolism, and psychopathology in overweight and obese schizophrenia and schizoaffective disorder subjects treated with a stable dose of olanzapine. During the 4 weeks of aripiprazole treatment, there were significant decreases in weight (P = 0.003) and body mass index (P = 0.004) compared with placebo. Total serum cholesterol (P = 0.208), high-density lipoprotein cholesterol (HDL-C; P = 0.99), HDL-2 (P = 0.08), HDL-3 (P = 0.495), and low-density lipoprotein cholesterol (P = 0.665) did not change significantly comparing aripiprazole treatment to placebo treatment. However, total serum triglycerides (P = 0.001), total very low-density lipoprotein cholesterol (VLDL-C; P = 0.01), and VLDL-1C and VLDL-2C (P = 0.012) decreased significantly during the aripiprazole treatment phase. The VLDL-3C tended lower during aripiprazole, but the decrease was not significant (P = 0.062). There was a decrease in C-reactive protein comparing aripiprazole treatment to placebo, although it did not reach significance (P = 0.087). The addition of aripiprazole to a stable dose of olanzapine was well tolerated and resulted in significant improvements on several outcome measures that predict risk for medical morbidity.
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PMID:Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. 2063 76


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