Clozapine has sub-micromolar affinity for 5-HT1A receptors in human brain tissue

doi:10.1016/0014-2999(92)90731-I

European Journal of Pharmacology

Volume 221, Issues 2–3, 20 October 1992, Pages 397-398

https://doi.org/10.1016/0014-2999(92)90731-I Get rights and content

Abstract

The affinities of a range of antipsychotic drugs at human hippocampal 5-HT_1A, receptors, defined by specific [³H]8-OH-DPAT binding, were determined. Clozapine demonstrated the highest affinity; all other antipsychotics studied demonstrated pK_i values below 6.0. 5-HT_1A receptors arc found on cortical glutamatergic neurons, a dysfunction of which may occur in schizophrenia. Binding at this site indicates a possible mechanism contributing to the unique efficacy of clozapine in the treatment of some schizophrenic patients.

References (7)

D.M. Bowen et al.
Treatment strategics for Alzheimer's disease
Lancet
(1992)
T. Nishikawa et al.
Increased [³H]kainic acid binding in the prefrontal cortex in schizophrenia
Neurosci. Lett.
(1983)
G.P. Reynolds
Developments in the drug treatment of schizophrenia
Trends Pharmacol. Sci.
(1992)

There are more references available in the full text version of this article.

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Mason and Reynolds reported that one of the major pharmacological therapeutic targets of clozapine is 5-HT1A receptors on cortical glutamatergic neurons (Mason and Reynolds, 1992). These authors suggested that clozapine binding to 5-HT1A receptors may contribute to the mechanism of the unique efficacy of clozapine in schizophrenic patients (Mason and Reynolds, 1992). Recent pharmacogenetics studies reported that a SNP (C-1019G: rs6295) in the promoter region of the 5-HT1A receptor gene (HTR1A), which regulates HTR1A transcription (Lemonde et al., 2003; Le Francois et al., 2008), is associated with improved response in negative symptoms with antipsychotics such as risperidone (Reynolds et al., 2006; Wang et al., 2008; Mossner et al., 2009).
Several investigations have reported associations between serotonin 1A (5-HT1A) receptor and major psychiatric disorders, such as schizophrenia and bipolar disorder (BP), making the 5-HT1A receptor gene (HTR1A) a good candidate gene for the pathophysiology of schizophrenia and BP. To evaluate the association between HTR1A and schizophrenia and BP, we conducted a case-control study of Japanese population samples with two single- nucleotide polymorphisms (SNPs), including rs6295 (C-1019G) in HTR1A. In addition, we conducted a meta-analysis of rs6295, which has been examined in other studies. Using one functional single- nucleotide polymorphism (SNP; rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (857 schizophrenic patients, 1028 BP patients and 1810 controls) in the Japanese population. Two association studies for schizophrenia and three association studies for BP, including this study, met our criteria for the meta-analysis of rs6295. We found an association between HTR1A and Japanese BP in a haplotype-wise analysis, the significance of which remained after Bonferroni correction. In addition, we detected an association between rs6295 and BP in the meta-analysis (fixed model: P(Z) = 0.000400). However, we did not detect an association between HTR1A and schizophrenia in the allele/genotype-wise, haplotype-wise or meta-analysis. HTR1A may play an important role in the pathophysiology of BP, but not schizophrenia in the Japanese population. In the meta-analysis, rs6295 in HTR1A was associated with BP patients.
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Stimulation of 5-HT1A receptors has been known to reduce the negative symptoms and cognitive dysfunction of schizophrenia (Meltzer et al., 2003; Meltzer and Sumiyoshi, 2008; Sumiyoshi et al., 2001, 2007). Mason and Reynolds (1992) reported that one of the major pharmacological therapeutic targets of clozapine is 5-HT1A receptors on cortical glutamatergic neurons. Several postmortem studies reported increased 5-HT1A receptor in the prefrontal cortex of schizophrenic patients (Burnet et al., 1996; Hashimoto et al., 1993, 1991; Simpson et al., 1996; Sumiyoshi et al., 1996).
Several investigations have reported associations the serotonin 1A (5-HT1A) receptor to schizophrenia and psychotic disorders, making 5-HT1A receptor gene (HTR1A) an adequate candidate gene for the pathophysiology of schizophrenia and methamphetamine (METH)-induced psychosis. Huang and colleagues reported that rs6295 in HTR1A was associated with schizophrenia. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes. In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue 1 (AKT1) gene was associated with METH-induced psychosis and schizophrenia in the Japanese population. Furthermore, we conducted an analysis of the association of HTR1A with METH-induced psychosis.
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Schizophrenia is a chronic, debilitating neuropsychological disease characterised by positive, negative, and cognitive deficits. In recent years, new pharmacological treatment strategies have been developed to treat the sequalae of schizophrenia based upon more selective receptor activity profiles in the hope that treatment efficacy can be increased without inducing the side-effect profiles seen with current available therapies. One such strategy involves the development of combined (partial) 5-HT_1A agonists and D₂ receptor (partial) antagonists such as bifeprunox, SLV313, F15063 and SSR-181507 in an attempt to increase therapeutic efficacy of all symptom domains whilst alleviating adverse side effects. Other novel drugs including SLV310 and SLV314 combine selective serotonin reuptake inhibition (SSRI) functionality with D₂ receptor antagonism in an attempt to not only improve schizophrenic symptoms, but to also relieve other affective disorders intricately linked with the disorder. The main scope of this review will evaluate the major preclinical and clinical pharmacological findings concerning the aforementioned strategies and pharmacological agents, and compare their therapeutic potential with currently available antipsychotics; however, recent developments at other emerging serotonergic targets such as 5-HT_2C, 5-HT₆ and 5-HT₇ receptors will also be considered.

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Rapid communicationClozapine has sub-micromolar affinity for 5-HT1A receptors in human brain tissue

Abstract

Lancet

Neurosci. Lett.

Trends Pharmacol. Sci.

Rapid communication
Clozapine has sub-micromolar affinity for 5-HT_1A receptors in human brain tissue