多巴胺D2受体-141C Ins/Del多态与海洛因渴求的关系

目的：探讨多巴胺D2受体-141C Ins／Del基因多态与线索诱发海洛因渴求程度的关系。方法：对戒断期380名海洛因依赖者实施线索诱发渴求实验，采用PCR-RFLP技术检测其DRD2-141C Ins／Del基因多态，比较不同基因型与线索诱发海洛因渴求程度的关系。结果：DRD2-141C Ins／Del三种多态基因型中，线索暴露前后海洛因渴求程度的差异均无显著性（P〉0．05）。结论：DRD2-141C Ins／Del基因多态可能与线索诱发海洛因渴求的易感性无关。     

Potential association of DRD2 and DAT1 genetic variation with heroin dependence

The aim of our study was to investigate the potential association of dopamine receptor D2 gene (DRD2) TaqI RFLP A (rs1800497) and dopamine transporter gene (DAT) 3′untranslated region VNTR genetic variations with heroin addiction. Genotyping was performed using PCR-based techniques in 530 heroin abusers and 500 controls. Our results showed that DRD2 TaqI A1 allele carriers (genotypes A1A1 and A1A2) were prone to heroin abuse in models of dominance or co-dominance. We detected a 12 repeat allele and 6/6, 7/9, 9/11, 10/12 genotype in a Chinese/eastern Asian population for the first time. However, no significant differences in the DAT1 VNTR were found between the two groups in either genotypic or allelic distributions and there was no gene interaction between the two genetic loci.     

Association analysis of the DRD4 and COMT genes in methamphetamine abuse.

We analyzed two polymorphisms in genes encoding proteins of the dopamine system, the Val158Met polymorphism in the catechol-O-methyltransferase gene and the 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene for association with methamphetamine abuse. We used a case/control design with 416 methamphetamine abusing subjects and 435 normal controls. All subjects were Han Chinese from Taiwan. We found an excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse. The 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show significant association with methamphetamine abuse. However, analysis of the 120-bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed significant association with methamphetamine abuse, which gave an empirical P value 0.0034 for a heterogeneity model. Moreover, there were significant interactive effects between polymorphisms in the catechol-O-methyltransferase and dopamine D4 genes. The evidence of interaction between COMT 158 Val/Met and DRD4 48-bp VNTR polymorphisms (P = 0.0003, OR = 1.45, 95% CI: 1.148-1.77), and between COMT 158 Val/Met and DRD4 120 bp promoter polymorphisms (P = 0.01, OR = 1.10, 95% CI: 1.10-1.18) were significant but the latter was weak. We conclude that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser.     

Dopamine D2 receptor polymorphisms and susceptibility to alcohol dependence in Indian males: a preliminary study

Background  

Dopamine is an important neurotransmitter involved in reward mechanism in the brain and thereby influences development and relapse of alcohol dependence. The dopamine D2 receptor (DRD2) gene on chromosome 11 (q22-q23) has been found to be associated with increased alcohol consumption through mechanisms involving incentive salience attributions and craving in alcoholic patients. Therefore, we investigated the association of three single nucleotide polymorphisms (SNP) in DRD2 gene with alcohol dependence in the north Indian subjects.     

Haplotype and allele frequencies for three genes of the dopaminergic system in South American Indians

Haplotype and allele frequencies for the dopamine D2 receptor gene (DRD2), dopamine D4 receptor gene (DRD4), and dopamine transporter protein gene (SLC6A3) were determined in 135 individuals from five Brazilian Indian tribes, and the results integrated with those previously presented for this ethnic group. DRD2 and DRD4 were highly polymorphic. Haplotypes including TaqI A1 at DRD2, and the seven repeat allele at DRD4 were the most frequent variants, while the SLC6A3 locus was monomorphic for the 10 repeat allele in South American Indians. Genetic distances and the corresponding neighbor-joining tree indicated a geographic dichotomy between North + Central American and South American natives, with the exception of the Wai Wai, who live north of the Amazon river and are grouped in the northern cluster. G_ST estimates from these genes vary between 0.05 and 0.11 for North and South America, respectively, indicating a higher degree of differentiation of the latter groups. These results are in accordance with previous genetic data on other systems, as well as with the history and biodemographical data of South American Indians. Am. J. Hum. Biol. 12:638–645, 2000. © 2000 Wiley-Liss, Inc.     

Relationship between dopaminergic neurotransmission, alcoholism, and Reward Deficiency syndrome.

In this review, we described the neural substrates underlying Reward Deficiency syndrome which, in turn, is posited to underlie alcohol dependency. Alcoholism is a complex, multifactorial disorder that results from the interplay between genetic and environmental factors. The D(2) dopamine receptor (DRD(2)) has been associated with pleasure, and the DRD(2) A1 allele has been referred to as a reward gene. Evidence suggests that there is a tripartite interaction involving dopamine receptor deficiency, a propensity to abuse alcohol, and reduced sensitivity to rewards. This interaction relies heavily on genetic characteristics of the individual, with certain ethnic groups having a greater tendency toward alcoholism than others. The DRD(2) has been one of the most widely studied in neuropsychiatric disorders in general, and in alcoholism and other addictions in particular. The dopamine D2 (DRD2) gene, and especially its allele TaqI A1 allele and its receptor, also may be involved in comorbid antisocial personality disorder symptoms, high novelty seeking, and related traits. The mesocorticolimbic dopaminergic pathway system plays an especially important role in mediating reinforcement by abused drugs, and it may be a common denominator for addictions such as alcoholism. When the mesocorticolimbic dopamine reward system dysfunctions (perhaps caused by certain genetic variants), the end result is Reward Deficiency syndrome and subsequent drug-seeking behaviors. Reward Deficiency syndrome refers to the breakdown of the reward cascade, and resultant aberrant conduct, due to genetic and environmental influences. Alcohol and other drugs of abuse, as well as most positive reinforcers, cause activation and neuronal release of brain dopamine, which can decrease negative feelings and satisfy abnormal cravings. A deficiency or absence of DRD(2) receptors then predisposes individuals to a high risk for multiple addictive, impulsive, and compulsive behaviors. Although other neurotransmitters (e.g., glutamate, gamma-aminobutyric acid (GABA), and serotonin) may be important in determining the rewarding and stimulating effects of ethanol, dopamine may be critical for initiating drug use and for reinstating drug use during protracted abstinence. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.     

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.     

Imaging gene–substance interactions: The effect of the DRD2 TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward

Dopamine is known as the main neurotransmitter modulating the activation of the reward system of the brain. The DRD2 TaqIA polymorphism is associated with dopamine D2 receptor density which plays an important role in the context of reward. Persons carrying an A1 allele have a lower D2 receptor density and a higher risk to show substance abuse. The present study was designed to investigate the influence of the DRD2 TaqIA polymorphism and the selective D2 receptor agonist bromociptine on the activation of the reward system by means of functional magnetic resonance imaging (fMRI). In a double-blind crossover study with 24 participants we found an increase of reward system activation from placebo to bromocriptine only in subjects carrying the A1 allele. Furthermore, only A1 carrier showed an increase of performance under bromocriptine. The results are interpreted as reflecting a specific sensitivity for dopamine agonists in persons carrying an A1 allele and may complement actual data and theories of the development of addiction disorders postulating a higher genetic risk for substance abuse in carrier of the A1 allele.     

Significant association of DRD2 enhancer variant rs12364283 with heroin addiction in a Pakistani population

The dopamine D2 receptor encoded by DRD2 has been implicated in multiple psychiatric disorders, mediated at least in part by two intronic variants affecting mRNA splicing, rs1076560 and rs2283265, and a less frequent enhancer variant, rs12364283, which increases DRD2 mRNA expression. This study tests whether these functionally validated variants confer susceptibility toward heroin addiction in a Pakistani population. A total of 540 heroin addicts and 467 healthy controls were genotyped, basic allele and genotype tests were performed. Neither rs1076560 nor rs2283265 significantly associated with heroin addiction. The enhancer rs12364283 occurs more frequently in heroin‐dependent cases than controls (MAF 13% vs. 7%, respectively), revealing significant association with heroin addiction (p = 3.0E‐06, OR 2.1). This study identifies rs12364283 of DRD2 as a potential risk factor for heroin addiction in the Pakistani study population. This enhancer variant had been shown to increase DRD2 mRNA expression, a possible factor in increased vulnerability to heroin addiction. Further studies are needed to validate this association of rs12364283.     

Gene-environment interaction in hyperkinetic conduct disorder (HD + CD) as indicated by season of birth variations in dopamine receptor (DRD4) gene polymorphism

Recently, an interaction between season of birth and the expression of candidate genes has been suggested. Season of birth variations in tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR) and the dopamine D4 receptor (DRD4) gene polymorphisms are different for affective disorders and schizophrenia. The DRD4 gene has been postulated as a candidate gene for attention-deficit-hyperactivity disorder (ADHD), equivalent to hyperkinetic disorder (HD). The seven-repeat long variant of this gene (DRD4*7) in comparison to the short repeat variants of the DRD4 gene polymorphism, has been found to be associated with ADHD. A seasonal pattern of birth has also been proposed for different subtypes of ADHD. Therefore, in a subgroup of children with HD and conduct disorder (CD) and in healthy controls, we investigated a possible association between the DRD4*7 allele and HD + CD in association with the season of birth. Supporting this hypothesis, we found an interaction between the seasons of birth and the expression of the DRD4 candidate gene in children with HD + CD as well as in controls, which differ significantly from each other. Depending on the season of birth, children carrying the DRD4*7R allele showed different relative risks for developing HD + CD.     

Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders

The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders.     

Association between novelty-seeking and the dopamine D3 receptor gene in bipolar patients: A preliminary report

Recent studies in healthy controls suggest an association between novelty-seeking (NS) and the dopamine D4 receptor (DRD4) gene. In this study, we further investigated the relationship between genes implicated in dopamine as well as serotonin neurotransmission and personality traits in bipolar (BP) disorder. Scores on the Tridimensional Personality Questionnaire were examined in 37 recovered Research Diagnostic Criteria-diagnosed BP patients genotyped for DRD3, DRD4, and serotonin 2A receptor (5HTR2a) polymorphisms. Carriers of DRD3 allele 1 showed significantly lower NS values compared to patients without this allele. Scores on NS and on harm-avoidance were not related to DRD4 or 5HTR2a polymorphisms. These preliminary results suggest a role for D3 receptor in NS expression in BP patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:192–194, 1998. © 1998 Wiley-Liss, Inc.     

Influences of polymorphic variants of DRD2 and SLC6A3 genes, and their combinations on smoking in Polish population

Background  

Polymorphisms in dopaminergic genes may influence cigarette smoking by their potential impact on dopamine reward pathway function. A1 allele of DRD2 gene is associated with a reduced dopamine D2 receptor density, and it has been hypothesised that A1 carriers are more vulnerable to smoking. In turn, the 9-repeat allele of dopamine transporter gene (SLC6A3) has been associated with a substantial reduction in dopamine transporter, what might result in the higher level of dopamine in the synaptic cleft, and thereby protective role of this allele from smoking. In the present study we investigated whether polymorphic variants of DRD2 and SLC6A3 genes and their combinations are associated with the smoking habit in the Polish population.     

No association between the dopamine D3 receptor gene and Korean alcohol dependence

The genes encoding dopamine receptor (DR) subtypes have received considerable attention for the past several years as a potential candidate that may affect susceptibility to addictive disorder, including alcoholism. The many association studies that compared the frequencies of alleles of the dopamine D2 receptor (DRD2) gene between alcoholics and control groups have produced results, but some have been equivocal. Dopamine D3 receptor genes (DRD3) are in the same class as DRD2 but with different pharmacological properties. So we compared the distribution of genotypes and frequencies of BalI polymorphism of the DRD3 gene in alcoholics and controls to assess the role of the DRD3 gene in Korean alcoholism. For this study, 67 male probands from alcoholics and 67 age-matched normal male controls were engaged. No evidence for an allelic association was found between the A1 allele of DRD3 and alcoholism in a Korean population. These results suggest that any role played by this receptor may account for only part of the variation in susceptibility to alcoholism.     

Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy

We decided to test the hypothesis that possibly by combining a narcotic antagonist and amino-acid therapy consisting of an enkephalinase inhibitor (D-phenylalanine) and neurotransmitter precursors (L-amino- acids) to promote neuronal dopamine release might enhance compliance in methadone patients rapidly detoxified with the narcotic antagonist Trexan (Dupont, Delaware). In this regard, Thanos et al. [J. Neurochem. 78 (2001) 1094] and associates found increases in the dopamine D2 receptors (DRD2) via adenoviral vector delivery of the DRD2 gene into the nucleus accumbens, significantly reduced both ethanol preference (43%) and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. This DRD2 overexpression similarly produced significant reductions in ethanol non-preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This work further suggests that high levels of DRD2 may be protective against alcohol abuse [JAMA 263 (1990) 2055; Arch, Gen. Psychiatr. 48 (1991) 648]. The DRD2 A1 allele has also been shown to associate with heroin addicts in a number of studies. In addition, other dopaminergic receptor gene polymorphisms have also associated with opioid dependence. For example, Kotler et al. [Mol. Phychiatr. 3 (1997) 251] showed that the 7 repeat allele of the DRD4 receptor is significantly overpresented in the opioid-dependent cohort and confers a relative risk of 2.46. This has been confirmed by Li et al. [Mol. Psychiatry 2 (1997) 413] for both the 5 and 7 repeat alleles in Han Chinese case control sample of heroin addicts. Similarly Duaux et al. [Mol. Psychiatry 3 (1998) 333] in French Heroin addicts, found a significant association with homozygotes alleles of the DRD3-Bal 1. A study from NIAAA, provided evidence which strongly suggests that DRD2 is a susceptibility gene for substance abusers across multiple populations (2003). Moreover, there are a number of studies utilizing amino-acid and enkephalinase inhibition therapy showing reduction of alcohol, opiate, cocaine and sugar craving behavior in human trials (see Table 1). Over the last decade, a new rapid method to detoxify either methadone or heroin addicts utilizing Trexan sparked interest in many treatment centers throughout the United States, Canada, as well as many countries on a worldwide basis. In using the combination of Trexan and amino-acids, results were dramatic in terms of significantly enhancing compliance to continue taking Trexan. The average number of days of compliance calculated on 1000 patients, without amino-acid therapy, using this rapid detoxification method is only 37 days. In contrast, the 12 subjects tested, receiving both the Trexan and amino-acid therapy was relapse-free or reported taking the combination for an average of 262 days (p < 0.0001F). Thus coupling amino-acid therapy and enkephalinase inhibition while blocking the delta-receptors with a pure narcotic antagonist may be quite promising as a novel method to induce rapid detox in chronic methadone patients. This may also have important ramifications in the treatment of both opiate and alcohol-dependent individuals, especially as a relapse prevention tool. It may also be interesting too further test this hypothesis with the sublingual combination of the partial opiate mu receptor agonist buprenorphrine.     

生物反馈结合线索暴露治疗降低海洛因依赖者药物线索反应

目的:了解生物反馈结合线索暴露治疗是否降低海洛因依赖者环境线索诱发渴求及心理生理反应.方法:采用前瞻性的队列研究将60例环境线索诱发心理渴求增高的康复期海洛因依赖者分成实验组(n=36)与对照组(n=24),对照组只进行劳教场所的常规帮教,实验组除帮教外进行12次生物反馈结合线索暴露治疗,评估治疗前后环境线索诱发心理渴求与心理生理反应情况.结果:两组治疗结束后,实验组环境诱发前、后的心理渴求,肌电和皮导得分均低于对照组[诱发前:心理渴求(3.06±7.26)mm vs.(22.32±20.26)mm、肌电(8.52±4.23)μV vs.(12.06±5.17)μV、皮导(2.14±1.43)μS vs.(4.61±2.24)μS;诱发后:心理渴求(6.97±10.30)vs.(33.14±25.40)mm、肌电(8.72±4.31)vs.(14.79±5.86)μV、皮导(2.15±1.33)vs.(4.49±2.59)μS,P≤0.01].结论:生物反馈结合线索暴露治疗可降低康复期海洛因依赖者渴求及环境诱发心理生理反应.     

Association study of MAO‐A,COMT, 5‐HT2A,DRD2, and DRD4 polymorphisms with illness time course in mood disorders

The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO‐A), catechol‐O‐methyltransferase (COMT), serotonin receptor 2A (5‐HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR‐based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA). We could not observe a significantly different time course. No demographic and clinical variables such as sex, age or polarity of onset, presence of psychotic features, genetic loading, or education level influenced the observed results. Our results suggest that MAO‐A, COMT, 5‐HT2A, DRD2, and DRD4 gene variants are not involved in susceptibility toward different time courses in mood disorders. © 2002 Wiley‐Liss, Inc.     

The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.     

传统抗精神病药物所致迟发性运动障碍的药理遗传学初步研究

目的：进一步探讨多巴胺D2、D3受体（dopamine D2,D3 receptor,DRD2,DRD3)功能基因多态性与迟发性运动障碍(tardive dyskinesia,TD）的相关性及各候选基因，同时包括五羟色胺2C受体（5－hydroxytryptamine 2C receptor,HTR2C）和锰超氧化物歧化酶（manganese superoxide dismutase,MnSOD）基因的相互作用对TD发生的影响。方法：使用异常不自主运动量表（abnormal involuntary movement scale,AIMS)评定精神分裂症（schizophrenia,CSH)患者有无TD及其严重程度，并采用简明精神病评定量表评定患者精神症状；应用聚合酶链反应－限制性片段长度多态性技术分析TD组和非TD组各候选基因等位基因和（或）基因型分布频率及其结合分布频率，并分析对AIMS总分值的影响。结果：各候选基因在SCH患者组以及TD和非TD组基因型分布均符合Hardy-Weinberg平衡定律；TD组HTR2C基因－697C（突变型）等位基因频率高于非TD组，差异有显著性（P＜0．05）；DRD2基因Taq I A1/A2、DRD3基因Ser9Gly和MnSOD基因Ala-9Val等位基因频率和基因型分布在TD组与非TD组之间差异均无显著性（P＞0．05）；仅DRD3突变型（Gly）和MnSOD野生型（Val）结合分布频率高于其它结合型，差异有显著性（P＜0．05）；但上述各候选基因不同等位基因和（或）基因型亚组间的临床学资料和AIMS总分值（TD值）差异均无显著性（P＞0．05）。结论：HTR2C基因启动区－697G→C单碱基置换可能是中国汉族男性SCH患者TD发生的易感因素；而SCH患者若同时携带DRD3基因9Gly突变型和MnSOD基因－9Val野生型等位基因可能增加了TD的易感性。