UMLS:C0036341 - FACTA Search

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

MDL 100,907 is a potent and selective antagonist of the 5-HT2A receptor which, unlike other antagonists at this receptor, has little affinity for the 5-HT2C receptor. We have investigated the antipsychotic potential of MDL 100,907 by examining its ability to antagonise different behavioural effects of amphetamine in rats. MDL 100,907 reversed the locomotor stimulant effects of amphetamine in rats without itself having any effect on locomotor activity. It also antagonised the disruptive effects of amphetamine on the development of latent inhibition. In contrast, MDL 100,907 had no effect on the discriminative stimulus properties of amphetamine, nor did it affect the ability of amphetamine to reduce the threshold required to sustain rewarding brain stimulation in the ventral tegmental area. This profile is different from that of typical and atypical neuroleptics, and also from other 5-HT2 receptor antagonists, which lack the selectivity of MDL 100,907. These results suggest that MDL 100,907 may have a unique interaction with dopaminergic systems and support the further development of selective 5-HT2 receptor antagonists as a novel therapeutic strategy for schizophrenia.
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PMID:Reversal of amphetamine-induced behaviours by MDL 100,907, a selective 5-HT2A antagonist. 878 96

We have recently developed a simplified and time-saving method to measure the magnitude of serotonin (5-hydroxytryptamine, 5HT)-amplified platelet aggregation and dense granule secretion (DGS) responses. To study the effects of neuroleptics on peripheral serotonergic function, we measured physiologic responsivity of the platelet 5HT2 receptor complex in schizophrenic patients (n = 27), both before and after haloperidol withdrawal, and also in normal volunteers (n = 18). In human platelets, 5HT amplifies the adenosine diphosphate (ADP)-induced platelet aggregation and DGS. Such an amplification was significantly enhanced in platelets from both normal volunteers and haloperidol-stabilized patients. Following haloperidol withdrawal, however, the magnitude of 5HT-amplified DGS response was no longer significant in drug-free patients, demonstrating a decreased serotonergic responsivity in schizophrenia. Moreover, in drug-free patients, the net changes of ADP-induced DGS, with and without the presence of 5HT, were correlated significantly and negatively with both Bunney-Hamburg psychosis ratings and Brief Psychiatric Rating Scale (total) scores, but not with scores on the Scale for the Assessment of Negative Symptoms. In the drug-free group, no significant difference of 5HT amplification was demonstrated between relapsed and nonrelapsed patients. The present finding thus suggests that drug-free schizophrenic patients may have a reduced physiologic responsivity mediated through the platelet 5HT2 receptor complex, which can be modified by haloperidol treatment. The pharmacologic action of haloperidol may derive in part from serotonergic mechanisms. The magnitude of 5HT-amplified DGS may be useful in the prediction of therapeutic outcome after haloperidol treatment.
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PMID:Decreased serotonergic responsivity in platelets of drug-free patients with schizophrenia. 887 8

5HT2A receptors were measured in the frontal cortex from schizophrenic and non-schizophrenic subjects. There was a decrease in the density of 5HT2A receptors in Brodmann's areas 8, 9 and 10 from the schizophrenic subjects. In addition, there was an age-dependent decrease in the density of 5HT2A receptors in Brodmann's areas 9 from the non-schizophrenic subjects, which was absent in the schizophrenic subjects. Available evidence does not suggest that the change in 5HT2A receptors in the schizophrenic subjects was a result of drug treatment before death. These data may indicate that decreased 5HT2A receptors in the frontal cortex are involved in the pathology of schizophrenia.
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PMID:Decreased frontal cortical serotonin2A receptors in schizophrenia. 888 41

We have investigated 5-HT1A (serotonin1A) and 5-HT2A (serotonin2A) receptor mRNA abundance and binding site densities in various neocortical and hippocampal regions of schizophrenics and control subjects. Age, agonal state (brain pH), and post mortem interval were included where necessary as covariates in our analyses. In schizophrenics, 5-HT1A binding site densities, determined autoradiographically by [3H]8-hydroxy-2,3-(dipropylamino)-tetralin ([3H]8-OH-DPAT), were significantly increased (+23%) in the dorsolateral prefrontal cortex, with a similar trend in anterior cingulate gyrus. These increases were not accompanied by any change in 5-HT1A receptor mRNA. No differences between the groups in [3H]8-OH-DPAT binding or 5-HT1A receptor mRNA were seen in superior temporal gyrus, striate cortex, or hippocampus. 5-HT2A binding sites, determined by [3H]ketanserin, were decreased in the dorsolateral prefrontal cortex (-27%) and parahippocampal gyrus (-38%) of schizophrenics, with a similar trend in cingulate gyrus, but not in superior temporal gyrus or striate cortex. 5-HT2A receptor mRNA abundance was reduced in schizophrenics in the dorsolateral prefrontal (-49%), superior temporal (-48%), anterior cingulate (-63%) and striate (-63%) cortices, but not in parahippocampal gyrus. Parallel analyses of rat brain tissue showed no changes in 5-HT1A or 5-HT2A receptor mRNAs or binding site densities after chronic administration of haloperidol. These data show that schizophrenia is associated with alterations in the expression of central 5-HT1A and 5-HT2A receptors. They confirm reports of increased 5-HT1A and decreased 5-HT2A binding site densities in prefrontal cortex, and reveal more extensive decreases in 5-HT2A receptor gene expression at the mRNA level. The resulting imbalance in the 5-HT1A to 5-HT2A receptor ratio, when considered in terms of the chemoarchitectural distribution of these receptors, may contribute to an impairment of corticocortical association pathways. The apparent dissociation of the normal relationships between the abundance of each 5-HT receptor and its mRNA in schizophrenia introduces a separate complexity to the data, which may give clues to the underlying molecular mechanisms.
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PMID:5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. 891 17

The antipsychotic drug risperidone shows high affinity for both central serotonin (5-HT)2A and dopamine (DA)-D2 receptors in vivo. By employing microdialysis in freely moving rats, the effects of acute risperidone administration on regional brain DA and 5-HT release and metabolism were compared with the corresponding effects of the atypical antipsychotic drug clozapine as well as amperozide, the selective DA-D2 receptor antagonist raclopride and the selective 5-HT2A/5-HT2C receptor antagonist ritanserin. Risperidone (0.2 or 2.0 mg/kg, SC) was found to increase DA release and metabolism to about the same extent in three major projection areas of the mesotelencephalic dopaminergic system, i.e. the nucleus accumbens (NAC), the medial prefrontal cortex (MPC) and the lateral striatum (STR). In contrast, clozapine and amperozide (both 10.0 mg/kg, SC), as well as raclopride (2.0 mg/kg, SC), were all found differentially to affect DA release and metabolism in the three projections areas. Specifically, clozapine and amperozide enhanced DA release in the MPC to a greater extent than in the NAC or the STR, whereas raclopride instead preferentially increased DA release in the NAC and the STR but not in the MPC. Ritanserin (3.0 mg/kg, SC) did not exert any major effects on DA metabolism in the three areas studied. In contrast to the regionally rather homogenous activation of brain DA systems caused by risperidone, the drug was found to enhance brain 5-HT metabolism preferentially in the MPC, as indicated by the elevated extracellular concentration of 5-hydroxyindoleacetic acid (5-HIAA) in this region. A similar elevation of the 5-HIAA level in the MPC was observed after amperozide and, to some extent, after clozapine and ritanserin administration. The risperidone-induced (2.0 mg/kg, SC) elevation of 5-HIAA concentrations in the frontal cortex was found to be paralleled by an increased 5-HT release in this brain area. Consequently, our findings demonstrate a pharmacological profile of risperidone, as reflected in brain DA metabolism, in between that of clozapine and the DA-D2 antagonists. The preferential activation of 5-HT release and metabolism in frontal cortical areas might be of particular relevance for the ameliorating effect of risperidone on negative symptoms in schizophrenia, especially when associated with depression.
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PMID:Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain. 893 2

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
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PMID:Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. 893 1

Increasing evidence suggests an important role of 5-HT, and 5-HT2A receptors in particular, in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study used the selective serotonin2A (5-HT2A) antagonist and putative antipsychotic agent MDL 100,907 to evaluate the contribution of 5-HT2A receptors to the disruptions of prepulse inhibition produced by several 5-HT agonists. The D2 antagonist haloperidol was used to evaluate a possible interaction with dopamine neurons. Sound or light prepulses were used to measure the generality of these drug effects on cross-modal prepulse inhibition. In the first study, MDL 100,907 antagonized the disruptions of auditory prepulse inhibition produced by the 5-HT releasing agents fenfluramine and 3,4-methylenedioxymethamphetamine (MDMA). These effects on prepulse inhibition were modality-specific in that MDL 100,907 did not reverse the effects of the 5-HT releasers on visual prepulse inhibition. Haloperidol did not alter the disruptive effects of MDMA or fenfluramine on either auditory or visual prepulse inhibition. In the second study, the direct acting 5-HT2A/2C receptor agonist/hallucinogen (+)1-4-iodo-2,5-dimethoxyphenyl-2-aminopropane (DOI) consistently disrupted auditory prepulse inhibition, and this effect was blocked by MDL 100,907 but not by haloperidol. A dose-response analysis demonstrated that MDL 100,907 potently antagonized DOI disrupted auditory prepulse inhibition, with an ED50 of 0.04 mg/kg, IP. DOI did not consistently disrupt visual prepulse inhibition. In summary, these data indicate that, at least under the conditions of the present studies, the disruptions of auditory prepulse inhibition produced by fenfluramine, MDMA, and DOI result from stimulation of 5-HT2A receptors. Furthermore, these disruptions do not involve direct or indirect stimulation of D2 receptors. The identity of the 5-HT receptor(s) underlying the disruptive effects of fenfluramine or MDMA on visual prepulse inhibition has not yet been identified. MDL 100,907 may be generally useful in CNS disorders in which excessive 5-HT2A receptor tone disrupts sensory gating processes.
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PMID:5-HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5-HT2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5-HT agonists in Wistar rats. 893 5

Nine monoamine receptor antagonists have been compared for their potency to inhibit both spontaneously occurring and DOI ((1-)2,5-dimethoxy-4-iodophenyl)-2-aminopropane)-induced head-shakes (HS). Ritanserin, ketanserin, prazosin, haloperidol, pimozide, SCH 23390 and SCH 39166 potently and dose-dependently antagonised both types of HS while sulpiride and raclopride produced weak and partial antagonism. The potency of these agents to inhibit spontaneous HS and DOI-induced HS was closely correlated (r = 0.94) and was significantly related to 5HT2A receptor and to alpha 1-adrenoceptor affinities taken from published sources. Potency was independent of affinity for D2 receptors but there was a possible influence of D1 receptor affinity. HS have been proposed to model Tourette's Syndrome; thus the present findings may have implications for the mechanism of action of antipsychotic agents in this condition and possibly also in schizophrenia. Contrary to previous suggestions, 5HT2A receptors may be tonically activated under physiological conditions.
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PMID:Similarities in the pharmacology of spontaneous and DOI-induced head-shakes suggest 5HT2A receptors are active under physiological conditions. 895 81

The influence of genetic factors in schizophrenia has been demonstrated by family, twin and adoption studies. The first-degree relatives of patients with schizophrenia have a risk of schizophrenia that is about 10 times greater than that of the general population. Concordance rate for schizophrenia is higher in monozygotic twins that in dizygotic twins. Biological relatives of individuals with schizophrenia have an increased risk of schizophrenia, although adoptive relatives have no increased risk. Many findings suggest the important role of serotonin (5-HT) in the pathophysiology of schizophrenia. Our direct analysis of 5-HT receptor genes in schizophrenia by single stranded conformational polymorphism revealed amino acid substitution in the 5-HT2A and 2C receptor genes. There is no association between the amino acid substitution in the 5-HT2A and 2C receptor genes and the antipsychotic response to clozapine, although both of the substitutions showed the functional influence of these receptors. So far linkage, affected sib pair and association studies have not been able to identify a susceptibility gene for schizophrenia. The molecular genetic approach to schizophrenia has been complicated by genetic heterogeneity, phenotypic heterogeneity and the small family size of this disorder.
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PMID:[Molecular genetic approach to schizophrenia: direct analysis of 5-HT receptor genes]. 896 36

Iloperidone (HP 873; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl]ethanone) is a compound currently in clinical trials for the treatment of schizophrenia. Iloperidone displays affinity for dopamine D2 receptors and for 5-HT2A receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic. Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes. We employed receptor binding assays using membranes from cells stably expressing human dopamine D1, D2S, D2L, D3, D4 and D5 and 5-HT2A and 5-HT2C receptors and rat 5-HT6 and 5-HT7 receptors. Iloperidone displayed higher affinity for the dopamine D3 receptor (Ki = 7.1 nM) than for the dopamine D4 receptor (Ki = 25 nM). Iloperidone displayed high affinity for the 5-HT6 and 5-HT7 receptors (Ki = 42.7 and 21.6 nM, respectively), and was found to have higher affinity for the 5-HT2A (Ki = 5.6 nM) than for the 5-HT2C receptor (Ki = 42.8 nM). The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds.
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PMID:Iloperidone binding to human and rat dopamine and 5-HT receptors. 899 30

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