海洛因依赖与多巴胺D2受体基因的关联分析

目的：探讨海洛因依赖与多巴胺D2受体基因的相关性。方法：应用聚合酶链反应-限制性片段长度多态性分析技术，检测302例海洛因依赖者和177名正常对照者的D2受体基因-141C Ins/Del多态性的基因型和等位基因频率。结果：共检测出三种基因型：纯合子-141C Del/Del(304bp、304bp)、杂合子-141C Ins/Del(304bp、160bp、144bp)、纯合子-141C Ins/Ins(160bp、144bp)。海洛因依赖组的-141C Ins/Del多态性的基因型频率与对照组的差异无显著性（X^2=5.33，P=0.07），但海洛因依赖组-141C Del等位基因频率（16.6％）高于对照组（11.0％；X^2=5.37，P=0.02）。结论：D2受体基因-141 Cins/Del多态性可能与海洛因依赖的易感性相关。     

细胞色素P4502D6及多巴胺D2受体基因多态性与利培酮疗效的关联

目的 探讨细胞色素P450 2D6(cytochromes P450 2D6,CYP2D6)基因多态性、多巴胺D2受体(dopamine D2 receptor,DRD2)基因多态性与利培酮疗效的相关性.方法 对199例首发精神分裂症患者给予利培酮治疗8周,治疗前后采用阳性和阴性症状量表(Positive and Negative Syndrome Scale,PANSS)评定疗效,同时收集198例正常对照进行病例-对照分析.采用聚合酶链反应序列特异性引物扩增技术检测CYP2D6/C188T、DRD2 TaqIA基因型,分析二者与利培酮临床效应的相关性.结果 病例组和对照组CYP2D6/C 188T的基因型和等位基因频率相比,差异有统计学意义(CC:40.7％ vs.21.2％,CT:25.6％ vs.45.5％,TT:33.7％vs.33.3％,P＜0.05;C:53.5％ vs.43.9％,T:46.5％ vs.56.1％,P＜0.05),病例组和对照组DRD2 TaqIA的基因型和等位基因频率相比,差异有统计学意义(A1A1:29.1％ vs.35.9％,A1A2:37.7％ vs.47.5％,A2A2:33.2％ vs.16.6％,P＜0.05; A1:48.0％ vs.59.6％,A2:52.0％ vs.40.4％,P＜0.05);CYP2D6/C 188T与DRD2TaqIA的交互作用对PANSS减分率的影响没有统计学意义(F=0.735,P＞0.05);CYP2D6/C188T,DRD2TaqIA与性别的交互作用对PANSS减分率的影响具有统计学意义(F=3.214,P＜0.05).结论 CYP2D6基因C188T多态性和DRD2基因TaqIA多态性不是影响精神分裂症患者利培酮临床疗效的易感因素,但是在协变量性别的作用下,上述基因多态性的交互作用可能影响利培酮的疗效.     

多巴胺D2受体TaqI A多态性与海洛因渴求程度的关联分析

目的探讨多巴胺D2受体TaqI A多态性与线索诱发海洛因渴求程度的关系.方法 380名海洛因依赖者接受环境诱发渴求实验,用PCR-RFLP技术检测DRD2受体TaqI A多态性,比较不同基因型与线索暴露前后渴求程度的关系. 结果强制戒毒被试者基因型与暴露前后渴求程度未见显示差异(P＞0.05).自愿戒断被试者基因型与诱发后渴求分值、暴露前后渴求分差值的差异有显著性(F=4.523,P=0.012;F=3.936,P=0.021),A1/A1基因型被试者暴露后渴求程度高于A2/A2(P=0.027,P=0.019)和A1/A2(P=0.032,P=0.035)被试者.三者基因型在成瘾、加量和海洛因使用时间差异上有显著性(P=0.014,P=0.001,P=0.004).A1/A1基因型个体成瘾时间和加量时间小于A2/A2(P=0.007,P=0.001)和A1/A2(P=0.023,P=0.001)基因型个体,但吸毒时间大于A1/A2(P=0.003)和A2/A2(P=0.002)基因型个体. 结论 DRD2受体基因TaqI A多态性可能与环境诱发海洛因渴求程度易感性和成瘾、加量及毒品使用时间有关,A2+(A2/A2,A1/A2)基因型可能在海洛因依赖中起保护作用,而A2-(A1/A1)基因型则可能具有促进作用.     

海洛因依赖与多巴胺D4受体基因的关联分析

家系研究、孪生子研究和寄养子研究结果表明,海洛因等非成瘾物质依赖受遗传和环境因素的共同影响.近年来,研究者们已开始对非成瘾物质依赖的易感基因进行了初步的探讨.许多研究证实成瘾行为的犒赏机制与中脑边缘/中脑皮层多巴胺通路有关,多巴胺受体基因也因此成为物质依赖易感性的主要候选基因之一.多巴胺d4受体基因外显子3的1个48bp片段的可变重复序列多态性(DRD4 VNTR)可能影响受体功能,一直以来备受多种精神疾病研究的关注.国外已有研究报告D4 VNTR长等位基因与酒中毒、海洛因依赖和男性非成瘾物质(大麻、可卡因、阿片等)的严重使用/滥用相关.本研究拟在中国汉族人群中探讨该多态性与海洛因依赖易感性的相关性.     

多巴胺D2受体基因多态性与利培酮疗效、锥体外系副反应及治疗前后泌乳素水平变化的关联分析

目的 探讨多巴胺D2受体基因Tqq1A多态性与利培酮的疗效、锥体外系副反应及治疗前后泌乳索水平变化的相关性.方法 纳入198例首发精神分裂症患者和198名健康对照,给予患者利培酮治疗8周;采用阳性和阴性症状量表和修改的Sampson氏锥体外系反应量表分别评定患者的疗效和锥体外系副反应(EPS);测定患者治疗前后泌乳素水平;检测所有受试者的D2受体基因Taq1 A多态性.结果 不同疗效组、有无EPS组的Taq1 A多态性基因型和等位基因频率差异均无统计学意义(P>0.05),不同基因型组和不同等位基因组患者之间治疗前后泌乳素升高的差异无统计学意义(P>0.05).结论 未发现D2受体基因Taq1 A多态性与利培酮的疗效、锥体外系副反应及治疗前后泌乳素变化存在关联.     

多巴胺D2受体基因的TaqI A多态性与迟发性运动障碍的关联分析

目的　研究多巴胺D2受体 (DRD2 )基因TaqIA多态性与精神分裂症伴迟发性运动障碍 (TD)的相关性。方法　使用异常不自主运动量表 (AIMS)评定精神分裂症患者有无TD及TD严重程度 ,并采用简明精神病评定量表 (BPRS)评定患者精神症状 ;应用聚合酶链反应 (PCR)—限制性片段长度多态性 (RFLP)法分析TD组和非TD组的DRD2基因的TaqIA等位基因频率和基因型分布。结果　DRD2基因TaqIA的等位基因频率和基因型分布在TD组与非TD组之间均无显著性差异 ,且不同基因型间的AIMS总分值也无显著性差异。结论　在中国汉族男性精神分裂症患者中DRD2基因的TaqIA多态性可能不是影响TD发生的主要危险因素。     

Mu阿片受体多态性与海洛因依赖的关联研究

目的：探讨上海汉族人群中Mu阿片受体（OPRMI）基因A118G位点、C1031G位点多态性与海洛因依赖关联性。方法：采用病例对照研究，分别检测201名海洛因依赖者（依赖组）和249名健康对照（对照组）OPRMI基因A118G和C1031G位点基因型及等位基因频率，分析海洛因依赖者OPRMI受体基因多态与物质依赖的相关性。结果：A118G和C1031G位点多态性在依赖组和对照组间的分布差异无显著性；单体型分析两位点4种单体型均与海洛因依赖间无关联。结论：OPRMI基因A118G和C1031G位点与海洛因依赖无显著相关性。     

多巴胺D2受体基因多态性与脑出血的相关性研究

目的 探讨多巴胺D2受体（DRD2）基因TaqI位点多态性与中国湖南地区汉族人群脑出血发病的相关性.方法 本研究筛选121例脑出血患者,匹配103例正常体检人群为对照,PCR-RFLP检测DRD2 TaqI基因多态性.结果 DRD2 TaqI三种基因型（A1A1,A1 A2,A2A2）频率及两种等位基因（A1,A2）频率在脑出血组和正常对照组分布的差异无统计学意义（P＞0.05）.脑出血组中高血压亚组、非高血压亚组及对照组三者两两比较DRD2 TaqI基因型频率分布的差异无统计学意义（P＞0.05）.Logistic回归调整了脑出血环境因素的影响后,DRD2 TaqI基因多态性仍与脑出血的无相关性（P＞0.05）.结论 DRD2 TaqI基因多态性可能与中国湖南地区汉族人群脑出血无关.     

海洛因依赖稽延性戒断症状的多因素回归分析

目的探讨海洛因依赖稽延性戒断症状的影响因素。方法以一般人口学资料、汉密顿焦虑量表(HAMA)、稽延性戒断症状评定量表(PWSRS)、症状自评量表(SCL-90)、人格诊断问卷(PDQ)、药物成瘾者生命质量量表(QOL-DA)、社会支持评定量表(SSRS)为评估工具,评估120例海洛因依赖者稽延性戒断症状的心理、社会因素;并测定去甲肾上腺素(NE)、多巴胺(DA)、5-羟色胺(5-HT)浓度,进行动态心电图24小时心率变异分析(HRV),评估生物学因素。结果海洛因依赖稽延性戒断症状主要受复吸、SCL-90躯体化、PDQ回避型、动态心电图RR间期的标准差(SDNN)、动态心电图低频功率与高频功率之比(LF/HF)、5-HT的影响,标准回归系数依次为:0.241、0.388、0.109、0.213、0.183、0.077。结论海洛因依赖者稽延性戒断症状受生物、心理、社会三方面的影响,因此治疗需采取综合治疗措施。     

多巴胺D2受体基因Taq1A多态性与利培酮、帕利哌酮所致高泌乳素血症的关系

目的:探讨多巴胺2(D2)受体基因Taq1A多态性与利培酮、帕利哌酮所致高泌乳素血症(HPRL)的关联性。方法:92例女性精神分裂症患者给予利培酮或帕利哌酮治疗4周,于治疗前后测定血清PRL水平及治疗后的9-羟利培酮血药浓度;并检测所有受试者的D2受体基因Taq1A多态性。结果:HPRL组(治疗后PRL水平≥3 500 m IU/L者,n=30例)与LPRL组(治疗后PRL水平3 500m IU/L者,n=37例)Taq1A基因型等位基因频率组间差异无统计学意义(χ~2=1.73,P=0.42);Taq1A 3种基因型(A1/A1,A1/A2及A2/A2)患者血清PRL水平治疗后均明显增高,但治疗前后差值比较,组间差异无统计学意义(F=1.40,P=0.26)。结论:未发现D2受体基因Taq1A多态性与利培酮、帕利哌酮所致HPRL存在关联。     

A DRD2 and ANKK1 haplotype is associated with nicotine dependence

To test the importance of the dopamine D2 receptor (DRD2) region in nicotine dependence, 150 smokers and 228 controls were genotyped for the DRD2 C957T, -141delC and ANKK1 TaqIA polymorphisms (rs6277, rs1799732 and rs1800497, respectively). The -141delC SNP did not show any association but both the C957T and TaqIA SNPs showed association at the allele, genotype, haplotype and combined genotype levels. The 957C/TaqI A1 haplotype was more than 3.5 times as likely to be associated with nicotine dependence compared with the 957T/TaqI A1 haplotype (P=0.003). Analysis of the combined genotypes of both SNPs revealed that individuals who were homozygous for the 957C-allele (CC) and had either one or two copies of the TaqI A1-allele were 3.3 times as likely to have nicotine dependence compared to all other genotype combinations (P=0.0003) and that these genotypes accounted for approximately 13% of the susceptibility to nicotine addiction in our population. Our findings suggest that the DRD2 C957T polymorphism and the ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility to nicotine dependence.     

The dopamine D2 receptor gene is a susceptibility locus for Parkinson's disease.

The dopamine D2 receptor (DRD2) gene has been proposed as a candidate gene underlying several psychiatric and neurologic disorders. The aim of the present study was to examine if selected polymorphisms in the DRD2 gene are associated with Parkinson's disease (PD). We determined the allelic frequencies for four polymorphisms located in the DRD2 gene in a sample of 135 patients with PD and 202 normal control subjects. No significant difference was observed in the allelic frequencies between patients with PD and control subjects with regard to the -141C Ins/Del and the Ser311/Cys311 variants. On the contrary, the A1 allele of the TaqIA polymorphism and the B1 allele of the TaqIB polymorphism were more frequent in patients with PD than in control subjects (control subjects: TaqIA A1 = 14.6%, TaqIB B1 = 10.6%; patients with PD: TaqIA A1 = 20.7%, TaqIB B1 = 17.4%). Patients carrying the A1 allele or the B allele had an increased risk of developing PD (TaqIA, odds ratio: 1.71, 95% confidence intervals: 1.08-2.73; TaqIB, odds ratio: 1.83, 95% confidence intervals: 1.12-3.02). The TaqIA and TaqIB polymorphisms were in strong linkage disequilibrium, suggesting that these two polymorphisms convey the same information about the risk of presenting with PD. Genetic variation in the DRD2 gene may influence the risk of developing PD, thus confirming that the DRD2 gene is a susceptibility locus for PD.     

Association of VNTR polymorphisms in the MAOA promoter and DRD4 exon 3 with heroin dependence in male Chinese addicts

Objective. To explore the involvement of variable number tandem repeat (VNTR) polymorphisms in the monoamine oxidase A (MAOA) promoter and exon 3 of the dopamine D4 receptor (DRD4) gene in heroin addiction modulate the vulnerability of individuals to heroin addiction. Methods. Eight hundred and ninety-four male heroin addicts without other psychiatric disorders, were recruited as subjects. Another community 180 males were selected randomly as controls. Results. The geno-distribution of the DRD4 exon 3 VNTR polymorphism in controls was in Hardy–Weinberg equilibrium (HWEχ²=0.925), but the distribution in heroin addicts was not (HWEχ²=28.35). The long-repeat alleles of the DRD4 exon 3 VNTR polymorphism were found more frequently in the heroin addicts (P=0.019). However, the long-repeat alleles of the MAOA promoter VNTR polymorphism were not (P=0.828). No interaction between these two VNTR polymorphisms was found by using multiple logistic regression analysis (P=0.261). Conclusion. The long-repeat allelic variants (>4-repeats) and 2-repeat allele of the DRD4 exon 3 VNTR polymorphism might be risk alleles for individual vulnerability to heroin addiction in Chinese men, but the MAOA promoter VNTR polymorphism does not mean that the partial dominant inherited mode might involved in the genetics of heroin dependence.     

Buprenorphine and methadone maintenance treatment of heroin addicts preserves immune function

Opiate addiction influences many physiological functions including immune responses. The objective of this study was to investigate the immune system function in heroin addicted patients submitted to methadone or buprenorphine maintenance treatment compared to untreated heroin addicts and healthy controls. Four groups were studied: group A included nine heroin addicted subjects, who were still injecting heroin; groups B and C were composed of 12 patients previously addicted to heroin, being treated with methadone (mean dosage 58+/-12.7 mg/day) or buprenorphine (mean dose 9.3+/-2.3mg/day) since at least 6 months; group D was composed of 15 sex and age matched healthy controls. Lymphoproliferation and peripheral mononuclear cell cultures production of the Th1 cytokines IL-2 and IFN-gamma, the Th2 cytokine IL-4, and of the pro-inflammatory cytokine TNF-alpha were evaluated in all the patients and controls. PHA-lymphoproliferation was lower in untreated heroin addicts than in controls, while it was normal in methadone and buprenorphine treated patients. An altered Th1/Th2 balance, characterized by reduced IL-4, IFN-gamma and TNF-alpha but normal IL-2 levels, was present in untreated heroin addicted subjects, while the Th1/Th2 balance was well conserved in the methadone and buprenorphine groups. These findings suggest that the immune system abnormalities in heroin addicted patients can be restored to almost normal values by controlled treatment with methadone and buprenorphine.     

Influences of a DRD2 polymorphism on updating of long‐term memory representations and caudate BOLD activity: Magnification in aging

A number of genetic polymorphisms are related to individual differences in cognitive performance. Striatal dopamine (DA) functions, associated with cognitive performance, are linked to the TaqIA polymorphism of the DRD2/ANKK1 gene. In humans, presence of an A1 allele of the DRD2/ANKK1‐TaqIA polymorphism is related to reduced density of striatal DA D2 receptors. The resource‐modulation hypothesis assumes that aging‐related losses of neurochemical and structural brain resources modulate the extent to which genetic variations affect cognitive functioning. Here, we tested this hypothesis using functional MRI during long‐term memory (LTM) updating in younger and older carriers and noncarriers of the A1‐allele of the TaqIa polymorphism. We demonstrate that older A1‐carriers have worse memory performance, specifically during LTM updating, compared to noncarriers. Moreover, A1‐carriers exhibited less blood oxygen level‐dependent (BOLD) activation in left caudate nucleus, a region critical to updating. This effect was only seen in older adults, suggesting magnification of genetic effects on functional brain activity in aging. Further, a positive relationship between caudate BOLD activation and updating performance among non‐A1 carriers indicated that caudate activation was behaviorally relevant. These results demonstrate a link between the DRD2/ANKK1‐TaqIA polymorphism and neurocognitive deficits related to LTM updating, and provide novel evidence that this effect is magnified in aging. Hum Brain Mapp 36:1325–1334, 2015. © 2014 Wiley Periodicals, Inc.     

Chronic cannabis use does not affect the normalization of hypothalamic-pituitary-adrenal (HPA) axis induced by methadone in heroin addicts

The hypothalamic-pituitary-adrenal (HPA) axis activity is usually altered by heroin use. In the present study we evaluated in one hundred twenty-one heroin addicts the effects of marijuana smoking on the normalization of HPA axis upon methadone treatment. The study showed that in heroin addicts who are chronic cannabis smokers a treatment with methadone lasting 12 months was able to normalize both plasma corticotropin (ACTH) and cortisol levels, as well as to control both heroin withdrawal symptoms and opioid craving. As expected in the same group of patients marijuana smoking and its craving were not reduced by methadone treatment. Our data confirm that methadone treatment outcomes are not modified by cannabis use and they add in the literature the evidence that chronic cannabis use is not able to affect the normalization of HPA axis upon methadone treatment in heroin addicts.     

DRD2 TaqIA polymorphism is associated with urinary homovanillic acid levels in a sample of spanish male alcoholic patients

The TaqIA1 allele of the dopamine receptor gene D2 (DRD2) has been associated with alcoholism, as well as with other addictive behaviours. The exact nature of how the presence of this allele can be a vulnerability factor in the development of alcoholism remains unclear. In this study we found that the presence in the DRD2 genotype of the TaqIA1 allele in Spanish alcoholics is associated with higher levels of urine homovanillic acid (HVA) when compared to patients homozygous for the TaqIA2 allele. A sample of 142 Spanish male alcoholic patients was split into 2 groups on the basis of the presence or absence of the A1 allele in their genotype. The urine sample was analyzed by high performance liquid cromatography (HPLC), and the concentration of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and vanilylmandelic acid (VMA) was determined. We found a statistical difference in the concentration of HVA between the groups, that suggests this polymorphism could be related to the variance of urine HVA levels.     

Maintenance treatment of opiate addicts

Maintenance treatment is now the most common treatment of opiate addicts in Germany. The principle of maintenance treatment is the administration of an opioid in order to suppress withdrawal symptoms and heroin craving. In this manner, maintenance treatment successfully reduces heroin abuse and directly associated risk behaviour. Only a minority of maintenance patients became opiate abstinent (including the maintenance drug). Racemic methadone is the most extensively evaluated maintenance drug. A differential indication between medical opioids has not been scientifically established. According to the German regulations psychosocial support is an obligatory part of maintenance treatment. Most opiate addicts suffer from comorbid mental and somatic diseases. Therefore psychiatric and somatic treatment is indicated and of proven value.     

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N‐[¹¹C]methyl)benperidol ([¹¹C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1?), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10–14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1? was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R‐selective [¹¹C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.     

The TaqIA polymorphism linked to the DRD2 gene is related to lower attention and less inhibitory control in alcoholic patients.

The TaqIA polymorphism linked to the DRD2 gene has been associated with alcoholism. The aim of this work is to study attention and inhibitory control as per the continuous performance test and the stop task in a sample of 50 Spanish male alcoholic patients split into two groups according to the presence of the TaqIA1 allele in their genotype. Our results show that alcoholics carrying the TaqIA1 allele present lower sustained attention and less inhibitory control than those patients without such allele.