The Influence of Dopaminergic Genetic Variants on D2-like Receptors in Drinkers

描述(申请人提供)：酒精中毒的特征是个人无法适当地控制自己的酒精消费。相当多的证据表明，多巴胺能遗传标记，如DRD2 TaqIA多态，调节多巴胺受体的功能和/或表达，与发生酒精中毒的风险增加有关(Noble等人，2003年)。拟议的试点研究的目的是获得申请NIH拨款所需的初步数据，以评估28名白人男性社交饮酒者的多巴胺能遗传变异DRD2 TaqIA A1等位基因、COMT Val/Val vs.Met、DRD4 VNTR7-Repeat等位基因和DAT VNTRSCL39 9-Repeat(vs.10-Repeat等位基因)与相关的自我报告情绪状态之间的关系。对于DAT，3‘非翻译区(SLC6A3)的可变数目串联重复序列(VNTR)多态将与具有9/9或10/10基因型的亚组一起检测；COMT(儿茶酚-O-甲基转移酶)亚组将根据Val/Val(快速代谢物)或Met等位基因(低代谢物)进行划分，DRD2 TaqIA A1亚组将被分为A1和A1-参与者，外显子3的DRD4 VNTR将被分成具有大于或少于7-重复等位基因的亚组。我们正在比较有上述等位基因副本的社交饮酒者和没有上述等位基因副本的社交饮酒者在两种情况下的DA D2样受体的可用性；在摄入酒精饮料和2.)在摄入了安慰剂饮料之后。我们将对比等位基因组和酒精如何改变自我报告的情绪，并使用正电子发射断层扫描来测量纹状体D2样多巴胺受体可用性(作为酒精反应多巴胺释放的标志)和[18F]FolyPride(D2样多巴胺受体的放射性示踪剂)的变化，以确定是否存在基于基因的差异对酒精挑战的反应。我们预计，与他们的同龄人相比，具有DRD2 TaqIA A1等位基因、DAT有9个等位基因、DRD4有&lt；7重复的DRD4和Val/Val COMT基因的社交饮酒者在安慰剂扫描期间对放射性示踪剂的BPND更低，在摄入酒精后纹状体受体的可获得性比他们的同龄人更低，因为释放的多巴胺将与放射性示踪剂竞争，与这些人大脑中更少的受体结合。到目前为止，还没有发表过研究基因是否会影响多巴胺受体在酒精挑战时的反应方式的研究。 与公共卫生相关：酗酒和依赖酒精仍然是一种世界性流行病。在美国，1730万成年人报告酗酒或依赖，12岁或12岁以上的美国人中略多于一半的人报告目前饮酒(SAMHSA，2009)。我们拟议的研究将使用非侵入性脑成像技术来调查遗传学在大脑对酒精的反应中所起的作用，以及可能与饮用酒精饮料相关的情绪状态；目的是识别使人们容易受到有害饮酒行为影响的潜在生物标志物。

DESCRIPTION (provided by applicant): Alcoholism is characterized by the inability of individuals to regulate their consumption of alcohol appropriately. Considerable evidence links dopaminergic genetic markers like the DRD2 TaqIA polymorphism, which modulates the function and/or expression of dopamine receptors, to the increased risk for developing alcoholism (Noble et al., 2003). The aims of the proposed pilot study are to acquire preliminary data needed to apply for an NIH grant to assess the relationship between the dopaminergic genetic variants DRD2 TaqIA A1 allele, COMT Val/Val vs. Met, DRD4 VNTR 7-repeat allele and DAT VNTR SCL39 9-repeat (vs. the 10-repeat allele), with central response to alcohol, and associated self-reported mood states in twenty-eight white male social drinkers. For DAT, the variable number of tandem repeat (VNTR) polymorphism of the 3' untranslated region (SLC6A3) will be examined with subgroups that have either the 9/9 or the 10/10 genotype; COMT (catechol-O- methyltransferase) subgroups will be divided based on Val/Val (rapid metabolizers) or Met allele (low metabolizers), DRD2 TaqIA A1 subgroups will be separated into A1+ and A1- participants and the DRD4 VNTR in exon 3 will be separated into subgroups that have either greater or fewer than the 7-repeat allele. We are comparing DA D2-like receptor availability in social drinkers with copies of the above mentioned alleles to those without under two conditions; 1.) after ingesting an alcoholic beverage and 2.) after ingesting a placebo beverage. We will contrast the allelic groups with how alcohol alters self-reported mood and use positron emission tomography to measure changes in striatal D2-like dopamine receptor availability (as a marker for dopamine release in response to alcohol) with [18F]fallypride (a radiotracer for D2-like dopamine receptors) to determine whether differences exist based on genotype in response to an alcohol challenge. We expect that the social drinkers with the DRD2 TaqIA A1 allele, DAT with 9 alleles, DRD4 with <7 repeats and the Val/Val COMT genotypes, as compared with their counterparts, will have lower BPND for the radiotracer during the placebo scan and a greater reduction in striatal receptor availability after ingestion of alcohol, relative to their counterparts because, released dopamine will compete with the radiotracer for binding to fewer receptors in the brains of these individuals. To date, there are no published studies examining whether genotype affects the way dopamine receptors respond during an alcohol challenge. PUBLIC HEALTH RELEVANCE: The abuse of and dependence on alcohol continues to be a worldwide epidemic. In the United States 17.3 million adults reported alcohol abuse or dependence and slightly more than half of Americans aged 12 or older reported being current drinkers of alcohol (SAMHSA, 2009). Our proposed study will use non-invasive brain imaging techniques to investigate the role that genetics play in the brain's response to alcohol and possibly the emotional states associated with consuming an alcoholic beverage; with the intention of identifying potential biomarkers that make people vulnerable to harmful drinking behaviors.