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)

Previous studies have suggested a disturbance in the cortical serotonergic (5-HT) system in schizophrenia; however, these studies have been confounded by suicide in the patients groups, which in itself is associated with alterations in the 5-HT system. In this study we characterized various components of the 5-HT system in 14 areas of the frontal and parietal cortex in tissue obtained at postmortem from aged chronically hospitalized nonsuicidal schizophrenics compared to age-matched controls. We found no differences between control and schizophrenic subjects in the density of 5-HT uptake sites or other markers of 5-HT innervation. In Brodmann areas 24 and 6 the concentration of 5-HT2A,C receptors was decreased in all schizophrenics regardless of their antipsychotic treatment history. In all other areas examined 5-HT2A,C receptor concentrations were dramatically decreased in schizophrenics patients on drugs at time of death, whereas those off drugs at death showed the same values as control subjects. The density of 5-HT1A receptors was increased in areas 24, 9a (caudal part of area 9), 44, and 6 in subjects with schizophrenia. Antipsychotic treatment did not appear to have a significant effect. Thus, the specific pattern of alterations in the 5-HT system in schizophrenia may depend on the patient population and on antemortem antipsychotic treatment. These data also provide evidence that regulation of the 5-HT2 receptor may be involved in antipsychotic action.
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PMID:Alterations in the cortical serotonergic system in schizophrenia: a postmortem study. 937 49

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.
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PMID:Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity. 940 19

Several studies have shown an association between schizophrenia and the C allele of a T-C polymorphism at nucleotide 102 and the 5HT2A receptor gene. In the present study we observed this association in a sample of 63 parent/offspring trios where the proband received a diagnosis of DSM-III-R schizophrenia using TDT analysis (chi2 = 6.26, P= 0.006, chi2 = 9.00, P=0.001 when one affected offspring was selected at random from each family, suggesting that the results are due to association rather than linkage). There was no significant difference between the transmission of C102 from heterozygous fathers and mothers, which fails to support a role for genomic imprinting in this effect. T102C does not result in an alteration of the amino acid sequence of the protein. We therefore screened the promoter of 5HT2A for polymorphisms using single-strand confirmation polymorphism analysis. An A-G polymorphism at -1438 that creates an HpaII restriction site was identified. This was found to be in complete linkage disequilibrium with T102C and is hence a candidate for the pathogenic variant in schizophrenia. Functional analysis of A-1438G using luciferase assay demonstrated significant basal promoter activity in 5HT2A expressing HeLa cells by both the A and G variants. However, comparison of the A and G variants showed no significant differences in basal activity nor when promoter activity was induced by cAMP and protein kinase C-dependent mechanisms.
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PMID:A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter. 949 12

Cognitive dysfunction, a symptom of schizophrenia, has been recently identified as an important measure of outcome in the treatment of this disorder. Drug-mediated symptom improvement, the traditional measure of treatment success for schizophrenia, typically fails to associate with modifications of cognitive dysfunction, resulting in a failure of the patient to reintegrate into society. A paradigm shift is now required in the conceptualization of treatment success away from symptom decrement and towards treatments that improve cognitive function. Clozapine treatment has been shown to provide a significantly greater improvement in several domains of cognitive function, especially attention and verbal fluency, compared with conventional neuroleptics, whereas risperidone appears to have a beneficial effect on working memory. These results may be because of the normalization of dopamine function by clozapine and antagonism of 5HT2 receptors.
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PMID:The cognitive efficacy of atypical antipsychotics in schizophrenia. 955 11

In the present study, we demonstrate that, in a concentration-dependent manner, M100907 (formerly MDL 100907, a highly selective 5-HT2A receptor antagonist and a purported atypical antipsychotic drug [APD]), but not its much less active stereoisomer M100009, completely prevents or markedly reverses the phencyclidine (PCP)-induced blockade of N-methyl-D-aspartate (NMDA) responses in pyramidal neurons of the medial prefrontal cortex (mPFC). Furthermore, the atypical APD clozapine, but not the typical APD haloperidol or raclopride (a selective dopamine D2,3 receptor antagonist), mimicked the action of M100907, preventing the PCP-induced effect. These results suggest that M100907 might be an antidote for treating the PCP-induced psychotomimetic state that closely resembles schizophrenia; they could also account for the antipsychotic potential of M100907. Furthermore, our results suggest that the prototype (clozapine) and a candidate (M100907) atypical APDs might be effective in ameliorating schizophrenic symptoms including cognitive and neuropsychological deficits, which are induced in humans who abuse PCP. We hypothesize that the ability of M100907 and clozapine to prevent or reverse the PCP-induced blockade of the NMDA receptor channel is attributed to their 5-HT2A receptors antagonizing property. Therefore, with further systematic studies, the ability of compounds to prevent or reverse PCP's blockade of NMDA responses may prove to be an effective electrophysiological model for screening potential atypical APDs and predicting their therapeutic efficacy in cognitive deficits.
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PMID:M100907 and clozapine, but not haloperidol or raclopride, prevent phencyclidine-induced blockade of NMDA responses in pyramidal neurons of the rat medial prefrontal cortical slice. 960 79

To investigate putative abnormalities of cortical 5-HT2A receptor density in schizophrenia, we used positron emission tomography and [18F]setoperone, a high-affinity 5-HT2A receptor radioligand, in 14 neuroleptic-free or -naive schizophrenic patients and in 15 normal controls. No significant difference between the groups was observed in the whole or regional cortical binding potential of [18F]setoperone, indicating an absence of major 5-HT2A receptor cortical density abnormalities in schizophrenics.
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PMID:No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET. 963 32

The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia. The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907, clozapine, olanzapine, raclopride, SCH23390). Further, brain monoaminergic biochemistry was characterised in rats and mice after various drug treatments. PCPA pretreatment did not significantly reduce MK-801-induced hyperlocomotion in any of the experiments performed; however in a meta-analysis of six experiments, the locomotion displayed by MK-801-treated animals was diminished 17% by PCPA pretreatment. The selective 5-HT2A receptor antagonist M100907 exerted a dose-dependent inhibition of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manner by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5-HTP). On the other hand, the inhibition of MK-801-induced hyperlocomotion exerted by the selective dopamine D-2 receptor antagonist raclopride or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment. The antipsychotics clozapine and olanzapine displayed a split profile. Hence, the inhibitory effect on MK-801-induced hyperlocomotion exerted by low doses of these compounds was diminished after PCPA pretreatment, while inhibition exerted by higher doses was unaffected by PCPA. These results suggest that (1) MK-801-induced hyperlocomotion is accompanied by an activation of, but is not fully dependent upon, brain serotonergic systems. (2) In the hypoglutamatergic state induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that is almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors other than 5-HT2A receptors. M100907, by blocking 5-HT2A receptors, unveils the inhibitory effect exerted on locomotion by these other serotonin receptors. (3) Dopamine D-2 receptor antagonistic properties of antipsychotic compounds, when they come into play, override 5-HT2A receptor antagonism. Possible implications for the treatment of schizophrenia with 5-HT2A receptor antagonists are discussed. It is hypothesized that treatment response to such agents is dependent on increased serotonergic tone.
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PMID:Rodent data and general hypothesis: antipsychotic action exerted through 5-Ht2A receptor antagonism is dependent on increased serotonergic tone. 972 Sep 68

Suicidality has been found to be associated with low pre- and postsynaptic serotonin functioning. The purpose of this study was to examine whether in acutely suicidal psychiatric inpatients, the blood serotonin concentration was related to the underlying psychiatric disorder and whether it was associated with changes in the affinity (dissociation constant, KD) or in the maximal binding capacity (Bmax) of the platelet serotonin2A receptor. We therefore determined the blood serotonin concentrations and the platelet serotonin2A receptor activities of 45 suicidal psychiatric patients and 20 healthy subjects. We found that the blood serotonin concentrations were significantly lower in suicidal patients compared to healthy subjects. In all diagnostic categories (affective disorder, schizophrenia and adjustment disorder) we noted a significantly higher maximal binding capacity of the platelet serotonin2A receptor. These findings support the notion that a reduction in the availability of serotonin and an upregulation of the serotonin2A receptors in psychiatric patients are associated with a loss of control over suicidal impulses.
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PMID:Upregulation of the platelet Serotonin2A receptor and low blood serotonin in suicidal psychiatric patients. 973 8

Schizophrenic and schizotypal patients exhibit deficits in the habituation and prepulse inhibition (PPI) of startle responses, providing operational measures of the sensorimotor gating or filtering deficits suggested to contribute to cognitive disorganization in these patients. In rats, hallucinogens, entactogens, and NMDA antagonists share the ability to both retard startle habituation and disrupt PPI. Extensive pharmacological studies in rats have indicated that the effects of hallucinogens on habituation are mediated by direct agonist actions at 5-HT2 receptors. The effects of the entactogens on both habituation and PPI reflect indirect agonist actions due to the stimulation of presynaptic serotonin release. These observations in rats have supported the development of 5-HT2A antagonists for the treatment of schizophrenia. Animal studies have shown that PPI is modulated by multiple interacting neurotransmitters, including dopaminergic, serotonergic, cholinergic, GABAergic, and glutamatergic systems within cortical, limbic, striatal, and brainstem structures. The effects of PCP and other NMDA antagonists on PPI are insensitive to either dopaminergic or serotonergic antagonists, but are reduced by atypical antipsychotics such as clozapine, olanzapine, and Seroquel. Thus, the PCP model of schizophrenia-like deficits in sensorimotor gating offers promise for the identification and neurobiological investigation of atypical antipsychotics. The cross-species study of homologous gating functions, such as habituation and PPI, in animal models and psychiatric patients provides novel opportunities for the exploration of neurobiological substrates relevant to the group of schizophrenias.
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PMID:Behavioral studies of hallucinogenic drugs in animals: implications for schizophrenia research. 975 37

1. Sex steroid hormones exert profound effects on mood and mental state. Thus, in women, oestrogen is thought to protect against depression and delay the onset of schizophrenia and Alzheimer's disease. 2. Our studies in the female rat show that oestradiol, in its positive feedback mode for gonadotrophin release, increases the expression of genes for the 5-hydroxytryptamine 5-HT2A receptor and the serotonin transporter (SERT) in the dorsal raphe nucleus and the density of 5-HT2A receptor and SERT sites in regions of the forebrain that, in the human, are concerned with cognition, mental state, emotion and memory. 3. In the male rat, castration decreases while oestrogen and testosterone, but not 5 alpha-dihydrotestosterone (5 alpha-DHT), increase the density of 5-HT2A receptors in forebrain. The fact that 5 alpha-DHT has no effect suggests that the action of testosterone depends on its conversion to oestradiol by aromatase. 4. In intact rats, the density of 5-HT2A receptors in cerebral cortex is significantly higher in pro-oestrous female than in male and dioestrous female rats, showing that the spontaneous, preovulatory surge of oestradiol that reaches a peak at 12.00 h of pro-oestrus also increases the density of 5-HT2A receptors in cortex. 5. Oestrogen and testosterone (by way of its conversion to oestrogen) also stimulate the expression of the arginine vasopressin gene in the bed nucleus of the stria terminalis of the rodent, a mechanism that plays a key role in olfactory memory. 6. These actions of sex steroid hormones are discussed in the context of genomic versus non-genomic mechanisms, the recent discovery that there are two oestradiol receptors with different distributions in brain, the significance of our findings for our understanding of the control of mood, mental state and memory and the mechanism by which oestrogen stimulation of the 5-HT2A receptor could delay the onset of Alzheimer's disease.
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PMID:Sex steroid control of mood, mental state and memory. 978 14


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