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)

Schizophrenia is a serious psychiatric illness with a life-time risk of approximately one percent. Many of the patients, but not all, benefit from treatment with anti-psychotic drugs known to block dopamine D2-like receptors. The use of conventional neuroleptics is, however, hampered by the risk of extrapyramidal side-effects. Tardive dyskinesia (TD) is usually regarded as the most serious of these drug-induced movement disorders due to its high prevalence and potentially irreversible nature. In this study, we have investigated the genetic variation of the dopamine D3 receptor gene (DRD3) as a putative risk factor for TD in schizophrenic patients receiving long-term anti-psychotic drug therapy. We found a high frequency (22-24%) of homozygosity for the Ser9Gly variant (allele 2) of the DRD3 gene among subjects with TD in both a cross-sectional and a longitudinal evaluation, as compared with the relative under-representation (4-6%) of this genotype in patients with no or fluctuating TD. This result indicates that autosomal inheritance of two polymorphic Ser9Gly alleles (2-2 genotype), but not homozygosity for the wild-type allele (1-1 genotype), is a susceptibility factor for the development of TD, an observation which may improve the understanding of the pathophysiological mechanisms of TD and influence the design and choice of future anti-psychotic drugs. The correlation between a serious motor side-effect and a genetic marker could lead to selection bias in the sampling of schizophrenic patients for genetic studies, and may therefore explain the apparent association reported between susceptibility for schizophrenia per se and homozygosity for the DRD3 gene.
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PMID:Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. 910 22

The D3 dopamine receptor is a member of the family of D2-like dopamine receptors. Since the cloning and identification of the D3 receptor in 1990, considerable progress has been made towards understanding the function of this novel site. Although some avenues of investigation have yielded more definitive results than others, studies to date indicate the D3 receptor is localized preferentially in limbic brain areas and affects locomotion and perhaps reinforcement and reward. A subpopulation of the receptors appear to be autoreceptors which modulate dopamine synthesis, release, and neuronal activity. These observations have led to the hypothesis that the D3 receptor may be an appropriate target in the treatment of neuropsychiatric disorders such as schizophrenia and drug addiction. The role of D3 sites in disease, however, remains to be established. Genetic association of D3 receptor polymorphisms with neuropsychiatric disorders have been proposed. Alterations in expression of D3 sites may occur in some diseases. Although the study of this receptor is clearly in the early stages, these findings lay the foundation for future investigation. In this review, dopamine D3 receptor brain localization, cellular signaling mechanisms, and associated behavior will be discussed. The potential role of the D3 site in neuropsychiatric disorders and as a therapeutic target is also addressed.
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PMID:The D3 dopamine receptor in cellular and organismal function. 948 28

Several lines of evidence suggest that the dopamine D3 receptor is involved in the pathophysiology of schizophrenia. The D3 receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine substitution in the N-terminus of the receptor. Shaikh and colleagues have reported a significant association between the DRD3 Ser9 allele and the Ser9/Ser9 genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser9 and the Ser9/Ser9 genotype were found to be significantly associated with schizophrenia, although these investigators could not confirm reports of excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser9/Ser9 genotype was more frequent in patients who did not respond to clozapine. These data represent the most comprehensive examination of DRD3 Ser9Gly in schizophrenia to date. We have therefore determined DRD3 Ser9Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have genotyped 68 schizophrenics participating in double-blind clozapine trials. We do not find that Ser9 is preferentially transmitted in schizophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, and do not replicate the association between DRD3 and clozapine response. These data suggest that allelic variation in DRD3 may not play a role in the pathophysiology of schizophrenia or in clozapine response.
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PMID:The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. 949 16

We performed a meta-analysis of over 30 case-control studies of association between schizophrenia and a bi-allelic, Bali polymorphism in exon 1 of the dopamine D3 receptor gene. We observed a significant excess of both forms of homozygote in patients (P = 0.0009, odds ratio (OR) = 1.21, 95% Confidence Interval (CI) = 1.07-1.35) in the combined sample of 5351 individuals. No significant heterogeneity was detected between samples and the effects did not appear to be the product of publishing bias. In addition we undertook an independent, family-based association study of this polymorphism in 57 parent/proband trios, taken from unrelated European multiplex families segregating schizophrenia. A transmission disequilibrium test (TDT) showed a significant excess of homozygotes in schizophrenic patients (P = 0.004, odds ratio (OR) = 2.7, 95% CI = 1.35-5.86). Although no significant allelic association was observed, a significant association was detected with the 1-1 genotype alone (P = 0.02, OR = 2.32, 95% CI = 1.13-4.99). In addition when the results of the family-based association study were included in the meta-analysis, the homozygosity effect increased in significance (P = 0.0002, OR = 1.23, 95% CI = 1.09-1.38). The results of the meta-analysis and family-based association study provide independent support for a relationship between schizophrenia and homozygosity at the Bali polymorphism of the D3 receptor gene, or between a locus in linkage disequilibrium with it.
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PMID:A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia. 957 38

The involvement of dopamine in the etiology of schizophrenia is suggested by a number of neurobiological and pharmacological data, the dopamine D3 receptor (DRD3) being selectively expressed in brain regions which may be specifically involved in the risk for schizophrenia. The gene coding for DRD3 has thus been extensively analyzed. Since the initial report providing substantial evidence for an association of homozygosity of either allele of the gene coding for DRD3 (BalI polymorphisms) with schizophrenia, a flurry of replicating studies has appeared, which have been split into confirmations and nonreplications in North European Caucasian, Mediterranean, Asian, American, and African populations. The involvement of DRD3 polymorphisms thus remains questionable, particularly as no linkage studies have favored a nonrandom segregation of DRD3 alleles and schizophrenia. We performed a metaanalysis from 29 independent samples, from 24 different association studies so far published, allowing the examination of 2,619 schizophrenic patients and 2,517 controls. No significant differences of genotype counts were noted between patients and controls for the whole sample, considering frequency of any genotype. Starting from the high variability of the genotypes in different geographical areas, the impact of ethnic heterogeneity was taken into account. When the studies were reorganized in five groups according to geographical origin of samples, both homozygosity and 1-1 genotype revealed significant heterogeneity (P < 0.05). We specifically found an excess of homozygosity and 1-1 genotype in schizophrenic patients only in the African and Caucasian groups (P < 0.05). The present analysis suggests a small but significant effect of DRD3 in the susceptibility to schizophrenia, at least in Caucasians.
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PMID:Meta-analysis of DRD3 gene and schizophrenia: ethnic heterogeneity and significant association in Caucasians. 967 78

In an association study of the Bal I polymorphism in the dopamine D3 receptor (DRD3) gene in a French Caucasian population, global comparison of patients with schizophrenia (n = 89, DSM-III-R criteria) and controls (n = 52) led to non-significant differences. However, the homozygosity was significantly more frequent in schizophrenic patients with lifetime substance abuse comorbidity (n = 36) as compared to patients with no history of substance abuse (P = 0.010) or to controls (P = 0.047) and in neuroleptic responder patients as compared to treatment-refractory patients (n = 19; P = 0.037). The combined characteristics treatment response and lifetime substance abuse were strongly associated with homozygosity. We propose that homozygosity for the Bal I polymorphism DRD3 gene is associated with predisposition to substance abuse and/or the pharmacosensitive characteristic of schizophrenia rather than with schizophrenia itself, an hypothesis in agreement with the positive association of this polymorphism with opiate dependence (see companion article by Duaux et al) and the involvement of DRD3 in both pharmacodependence mechanisms and antipsychotic effects of neuroleptics.
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PMID:Dopamine D3 receptor gene variants and substance abuse in schizophrenia. 970 43

Anti-schizophrenia agents with improved efficacy and side-effect profiles are required. A dopamine D3 receptor agonist, R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3- b]-1,4-oxazin-9-ol HCl ((+)-PD 128,907), displayed an atypical antipsychotic profile comparable to that of clozapine. (+)-PD 128,907 blocked stereotypy produced by dizocilpine (MK-801) at 12-fold lower doses than those affecting apomorphine-induced stereotypes in mice and did not produce catalepsy. These effects of (+)-PD 128,907 were stereospecific and were blocked by a D3 antagonist. These data suggest a role for D3 receptors in antipsychotic drug action.
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PMID:Atypical antipsychotic-like effects of the dopamine D3 receptor agonist, (+)-PD 128,907. 974 97

The role of the dopamine D3 receptor subtype in the central nervous system is still not well understood. It has a distinct and restricted distribution, mostly associated with limbic territories of the striatum (olfactory tubercle and the shell of nucleus accumbens) in rat brain. Dopaminergic denervation induced by a 6-hydroxydopamine lesion of the nigrostriatal system in rat down-regulates the expression of the D3 receptor. In the present study, we investigated the functional neuroanatomy of the dopamine D3 receptor subtype in the monkey (Macaca fascicularis) basal ganglia. We also studied the effect of administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and chronic D1-like (SKF 82958) or D2-like (cabergoline) agonist treatments on dopamine D3 receptor levels using receptor autoradiography. Our results clearly show that the distribution of D3 receptors in the monkey is more closely related to associative and limbic components of the striatum (caudate-putamen), as compared with its sensorimotor counterpart. Hence, D3 receptors may be more specifically involved in cognitive and motivational aspects of striatal functions, which are elaborated in prefrontal, temporal, parietal, cingulate and limbic cortices. Moreover, MPTP administration significantly decreased levels of D3 receptors and this effect was reversed or compensated by a chronic treatment with a D1-like, but not a D2-like, receptor agonist. The D3 receptor may represent an important target for adjunct or direct therapy designed to improve cognitive deficits observed in patients with Parkinson's disease, schizophrenia and other illnesses with frontal lobe cognitive disturbances.
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PMID:Associative and limbic regions of monkey striatum express high levels of dopamine D3 receptors: effects of MPTP and dopamine agonist replacement therapies. 976 87

Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant (chi2 = 19.1, d.f. 4, P = 0.0008) due to an excess of the DRD3ser-gly genotype in the schizophrenia patients with TD. The difference between the schizophrenia patients with TD and the controls was highly significant (chi2 = 19.0, d.f. 2, P = 0.00007), even after correction for multiple testing, as was the difference between the combined group of schizophrenia patients and the controls (chi2 = 12.2, d.f. 2, P = 0.002). Comparing the schizophrenia patients with and without TD, genotypes containing the gly allele (DRD3ser-gly and DRD3gly-gly genotypes combined) were significantly associated with dyskinesia (OR = 2.62, 95% CI 1.18-5.59, P = 0.02). DRD3 genotype and age at first antipsychotic treatment contributed significantly to total score on the Abnormal Involuntary Movements Scale (AIMS). The contribution of DRD3 to the variance in AIMS total was 5.2% and the total proportion of the variance accounted for by these two variables together was 11.9%. These results support and extend the report by Steen et al (1997) of an association between DRD3 and TD in schizophrenia patients.
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PMID:Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia. 1039 14

A putative association of schizophrenia with a Msc I restriction fragment length polymorphism at the dopamine D3 receptor gene locus (DRD3) was tested among Indian families, using haplotype relative risk analysis and the transmission disequilibrium test (n=66 families and 58 sets of transmissions, respectively). A significant association either with homozygosity or with allele 1 at the biallelic polymporphism could not be detected.
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PMID:Association study of schizophrenia among Indian families. 1040 93


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