D2 dopamine receptor polymorphism and brain regional glucose metabolism

Positron emission tomography (PET) studies have shown decreased glucose metabolism in brain regions of detoxified alcoholics and cocaine abusers. However, it is not clear whether this decrease is due to chronic drug abuse or a pre-existing condition. Molecular genetic studies have found an association of the D₂ dopamine receptor (DRD2) A1 allele with alcoholism and drug abuse. Moreover, reduced central dopaminergic function has been suggested in subjects who carry the A1 allele (A1⁺) compared with those who do not (A1⁻). In the present study, using ¹⁸F-deoxyglucose, regional glucose metabolism was determined in healthy nonalcohol/nondrug-abusing subjects with the A1⁺ or A1⁻ allele. The mean relative glucose metabolic rate (GMR) was significantly lower in the A1⁺ than the A1⁻ group in many brain regions, including the putamen, nucleus accumbens, frontal and temporal gyri and medial prefrontal, occipito-temporal and orbital cortices. Decreased relative GMR in the A1⁺ group was also found in Broca's area, anterior insula, hippocampus, and substantia nigra. A few brain areas, however, showed increased relative GMR in the A1⁺ group. Since polymorphism of the DRD² gene is commonly observed in humans, the importance of differentiating A1⁺ and A1⁻ alleles subjects in PET studies is suggested. Am. J. Med. Genet. 74:162–166, 1997. © 1997 Wiley-Liss, Inc.     

D2 and D4 dopamine receptor polymorphisms and personality

The relationship of various dimensions of temperament, measured by the Tridimensional Personality Questionnaire (TPQ), to polymorphisms of the D₂ dopamine receptor (DRD2) and D₄ dopamine receptor (DRD4) genes was determined in 119 healthy Caucasian boys who had not yet begun to consume alcohol and other drugs of abuse. Total Novelty Seeking score of the TPQ was significantly higher in boys having, in common, all three minor (A1,B1, and Intron 6 1) alleles of the DRD2 compared to boys without any of these alleles. Boys with the DRD4 7 repeat (7R) allele also had a significantly higher Novelty Seeking score than those without this allele. However, the greatest difference in Novelty Seeking score was found when boys having all three minor DRD2 alleles and the DRD4 7R allele were contrasted to those without any of these alleles. Neither the DRD2 nor the DRD4 polymorphisms differentiated total Harm Avoidance score. Whereas subjects having all three minor DRD2 alleles had a significantly higher Reward Dependence 2 (Persistence) score than subjects without any of these alleles, no significant difference in this personality score was found between subjects with and without the DRD4 7R allele. In conclusion, DRD2 and DRD4 polymorphisms individually associate with Novelty Seeking behavior. However, the combined DRD2 and DRD4 polymorphisms contribute more markedly to this behavior than when these two gene polymorphisms are individually considered. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:257–267, 1998. © 1998 Wiley-Liss, Inc.     

湖南地区汉族人多巴胺D4受体基因48 bp可变数目串联重复多态性分布

目的 了解湖南地区汉族人群多巴胺D4受体（dopamine D4 receptor，DRD4）基因48 bp可变数目串联重复（variable number tandem repeat,VNTR）多态性基因型及等位基因的频率分布。方法 随机抽取湖南地区304名汉族健康正常人，采用聚合酶链反应、变性聚丙烯酰胺凝胶电泳结合银染技术检测基因型和等位基因的频率。结果 （1）湖南汉族人群DRD4基因48 bp VNTR多态性共检测出7种等位基因、12种基因型。最常见的等位基因是5等位基因（DRD4＊5），频率为70．6％。（2）湖南汉族人群DRD4基因48 bp VNTR多态性各等位基因频率与中国上海、北京、四川地区人群存在明显的差异。（3）湖南汉族人群DRD4基因48 bp VNTR多态性各等位基因频率与日本、美国、墨西哥、意大利人群也存在明显差异。结论 DRD4基因48 bp VNTR多态性分布存在不同程度的地区差异和种族差异。     

The D2 dopamine receptor gene: A review of association studies in alcoholism

Following our initial observation that theAl allele of the D₂ dopamine receptor (DRD2) gene was associated with alcoholism, a number of studies, both in the United States and abroad, have attempted to replicate and extend this finding in different Caucasian populations. In nine independent studies containing a total of 491 heterogeneous alcoholics (less severe and severe) and 495 heterogeneous controls (assessed and unassessed for alcoholism), the prevalence of theAl allele was 43.0% in the former group compared to 25.7% in the latter group (odds ratio=2.18, p<10^–7). The prevalence of theAl allele increased to 56.3% in a more homogeneous sample of 158 severe alcoholics (odds ratio =3.32,p<10^–8). Moreover, theBl allelle of theDRD2 gene was also found to be significantly associated with severe alcoholism. Additional data are accruing which also implicate theDRD2 Al andBl alleles in substance use disorders other than alcoholism. If further studies continue to support the results currently at hand, they would indicate that theDRD2 gene is the most prominent single gene determinant of susceptibility to severe substance abuse. However, the larger role still appears to be played by a combination of environmental factors and as yet unidentified genes.     

Structural change in dopamine D2 receptor gene in a patient with neuroleptic malignant syndrome

Dysfunction of the dopaminergic system has been suggested as a pathogenic mechanism in neuroleptic malignant syndrome. Therefore, we examined the complete coding sequences of the dopamine D₂ receptor (DRD₂) gene for structural abnormalities in 12 patients with a history of NMS, including two cases of familial NMS. Mutational analysis was performed by denaturing gradient gel electrophoresis (DGGE), a highly sensitive technique for detecting sequence differences. We found in one patient with a history of NMS a nucleotide substitution at codon 310 (CCG→TCG) of exon 7 of the DRD₂ gene which predicts the replacement of proline to serine in the third cytoplasmic loop of the receptor, a part of the receptor that interacts with G-proteins. A larger series of patients with NMS needs to be investigated to establish whether this allele is associated with an increased susceptibility to NMS. © 1995 Wiley-Liss, Inc.     

多巴胺受体D2型基因启动区多态性与精神分裂症关联研究

目的探讨湖北武汉地区汉族人群中多巴胺受体D2型基因(dopamine receptor D2, DRD2)启动区-141位点胞嘧啶插入/缺失多态性与精神分裂症的关联关系.方法应用聚合酶链反应-限制性片段长度多态性方法,对120例精神分裂症患者、100名健康对照者进行基因分型.对精神分裂症患者的 DRD2 -141位点胞嘧啶插入/缺失多态性进行了相关分析.结果 DRD2型基因启动区-141位点的等位基因、基因型频率在精神分裂症组与对照组之间的分布差异有统计学意义(P<0.05).在精神分裂症组中,-141C缺失的等位基因频率为0.11,对照组为0.18(比值比为0.55,95%可信区间为0.30～0.96,P <0.05).结论 -141位点胞嘧啶插入/缺失多态性非独立性地对精神分裂症与 DRD2基因的相关性产生修饰作用.-141位点胞嘧啶缺失可能是湖北武汉汉族精神分裂症患者的保护因素之一.     

No evidence of association between structural polymorphism at the dopamine D3 receptor locus and alcoholism in the Japanese

Dopaminergic systems mediate reward mechanisms and are involved in reinforcing self-administration of dependence-forming substances, including alcohol. Studies have reported that polymorphisms of the dopamine D2 receptor, whose structure and function are similar to those of the dopamine D3 receptor, increase the susceptibility to alcoholism. These observations led to the examination of the possible association between a structural polymorphism of the D3 receptor gene and alcoholism. Genotyping results, employing a PCR-RFLP method, showed no difference in allele and genotype frequencies of the D3 BalI polymorphism (Ser⁹/Gly⁹) between Japanese alcoholics and controls. Moreover, these frequencies were not altered in alcoholics with inactive aldehyde dehydrogenase-2 (ALDH2), a well-defined negative risk factor for alcoholism. These results strongly suggest that the dopamine D3 receptor is not associated with alcoholism. © 1996 Wiley-Liss, Inc.     

Association between three functional polymorphisms of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia

The dopamine D2 receptor (DRD2) gene is considered one of the candidate genes contributing to the development of tardive dyskinesia (TD). In the present study, we investigated the genetic association between three functional polymorphisms (Ser311Cys, ?141C Ins/Del and TaqI A) in the DRD2 gene and TD (200 patients with schizophrenia: 44 with TD and 156 without TD). No significant difference in the allelic and genotypic distribution between patients with TD and those without TD was observed. However, we found a slightly significant association between the ?141C Ins/Del polymorphism and the total Abnormal Involuntary Movement Scale (AIMS) score (P = 0.037). The significant association between the ?141C Ins/Del polymorphism and the total AIMS score did not remain after the regression analysis was taken into account (P = 0.14). Our results suggest that that three functional polymorphisms in DRD2 may not play a major role in the occurrence of TD. © 2001 Wiley‐Liss, Inc.     

Localization of dopamine D1A and D1B receptor mRNAs in the forebrain and midbrain of the domestic chick

The distribution and cellular localization of dopamine D1A and D1B receptor mRNAs in the forebrain and midbrain of the domestic chick were examined using in situ hybridization histochemistry with ³⁵[S]-dATP labeled oligonucleotide probes, visualized with film and emulsion autoradiography. Labeling for D1A receptor mRNA was intense in the medial and lateral striatum, and moderately abundant in the pallial regions termed the archistriatum and the neostriatum, in the hypothalamic paraventricular nucleus region, and in the superficial gray layer of optic tectum of the midbrain. D1B receptor mRNA was abundant in the medial and lateral striatum, and in the pallial region termed the hyperstriatum ventrale, and moderately abundant in the intralaminar dorsal and posterior thalamus and in the superficial gray of the optic tectum. At the cellular level, about 75% of neurons in the medial striatum and 59% of neurons in the lateral striatum were labeled for D1A receptor mRNA, whereas about 39% of the neurons in the medial striatum and 21% in the lateral striatum were labeled for D1B receptor mRNA. Large striatal neurons were not labeled for D1A or D1B receptor mRNA. The data suggest that while both D1A and D1B receptors mediate dopaminergic responses in many neurons of the avian striatum, primarily D1A receptors mediate dopaminergic responses in the archistriatum and the neostriatum, while primarily D1B receptors mediate dopaminergic responses in the hyperstriatum ventrale and the thalamus.     

Immunostimulating effect of quinpirole,a D2 dopamine receptor agonist

Laboratory of Mechanisms of Neurochemical Modulation, Institute of Physiology, Siberian Branch, Academy of Medical Sciences of the USSR, Novosibirsk. (Presented by Academician of the Academy of Medical Sciences of the USSR Yu. P. Nikitin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 109, No. 4, pp. 374–376, April, 1990.     

Association of dopamine receptor D5 gene polymorphism with peculiarities of voluntary attention in schizophrenic patients and their relatives

We studied the relationship between DRD5 gene polymorphism presented by microsatellites with cognitive signs in 152 schizophrenic patients, 81 mentally healthy relatives, and 125 mentally healthy control individuals. An association was found between DRD5 polymorphism with efficiency of visual voluntary attention in patients (p=0.02) and their relatives (p=0.006). Carriers of two copies of the 148-b.p. allele were characterized by low efficiency of attention. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 1, pp. 71–73, January, 2008     

Association between early-onset alcoholism and the dopamine D2 receptor gene

We examined the allelic association between the dopamine D2 receptor (DRD2) gene and alcoholism in 100 biologically unrelated Japanese alcoholics and 93 unrelated controls. Genomic DNA was prepared from peripheral white blood cells using the phenol-chloroform method. A 310-bp region surrounding the TaqA site at the DRD2 locus was amplified by polymerase chain reaction (PCR), and the PCR product was incubated with TaqI. The A1 allele remained intact while the A2 allele was cut. The frequency of the A1/A1 genotype and the frequency of the A1 allele were higher in early-onset alcoholics than in controls, P < 0.05 and P < 0.01, respectively. Moreover, the frequency of the A1/A1 genotype and the frequency of the A1 allele were higher in early-onset alcoholics with family histories of alcohol dependence than in controls, P < 0.01 and P < 0.01, respectively. The results indicate that the DRD2 gene is associated with susceptibility to early-onset alcoholism, and that each additional A1 allele shifts onset of alcoholism to an earlier age. Am. J. Med. Genet. 74:179–182, 1997. © 1997 Wiley-Liss, Inc.     

5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: Interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms

We recently reported an association between the long repeat allele of the dopamine D4 exon III receptor polymorphism and a human personality dimension, novelty seeking, as measured by the tridimensional personality questionnaire (TPQ), a personality instrument designed by Cloninger to reflect heritable facets of human temperament. The D4 receptor polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT_2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT_2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT_2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT_2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT_2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT_2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort. Am. J. Med. Genet. 74:65–72, 1997. © 1997 Wiley-Liss, Inc.     

Association study between the dopamine D4 receptor gene and schizophrenia

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic cloza-pine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48)_n bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed. © 1995 Wiley-Liss, Inc.     

No association of a functional polymorphism in the dopamine D2 receptor promoter region with bipolar or unipolar affective disorders

The dopaminergic system, along with the serotonergic and noradrenergic systems, has been implicated in the etiology of mood disorders. An association study of a functional variant in the promoter region of the dopamine D2 receptor (DRD2) with bipolar affective disorder I or unipolar major affective disorders was performed. Variable expression of the DRD2 gene in vitro has been shown with this promoter polymorphism. One hundred and thirty-one unrelated bipolar patients, 128 unrelated unipolar patients, and 262 controls were used in the study. There were no significant differences in DRD2 allele or genotype frequencies between the affective disorder and control groups. These results do not support a major role for the DRD2 gene in the etiology of either bipolar or unipolar affective disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:385–387, 1998. © 1998 Wiley-Liss, Inc.