Translational study on CHRNA5 variation and alcohol reward mechanisms

酒精使用障碍(AUD)是美国可预防死亡的第三大原因。这 疾病对受影响个人的健康、工作和人际关系有负面影响。关于网络信息技术的研究 酒精反应的遗传和环境决定因素及其与高血压风险的关系 发展澳元对于减少澳元的巨大社会负担至关重要。基因研究表明 AUD与多个基因座基因变异的相关性研究然而，由于AUD临床上的异质性 表型和小效应大小，人们对检测基因的影响越来越感兴趣 定量内表型的变异，如饮酒、饮酒和脑回路改变。 目前的应用集中在CHRNA5基因变异的潜在影响上。 编码烟碱型乙酰胆碱受体α5亚单位在酒精自我给药和脑回路中的作用 改装。CHRNA5中rs16969968错义单核苷酸多态(SNP)与 尼古丁成瘾和吸烟相关后果。然而，尽管普遍存在共同滥用 对于烟草和酒精，很少有人研究这种SNP对酒精使用、依赖或 酒精反应。这项建议的目标是研究CHRNA5变异对酒精的影响 使用集成的翻译药物遗传学方法进行响应，该方法利用 NIAAA和NIDA内部计划的研究人员与PI项目结合起来进行临床研究 啮齿动物模型中的人类受试者和临床前分析。一项前瞻性研究将比较酒精本身 G等位基因纯合的人类给药行为和神经影像反应 这些都是CHRNA5 rs16969968 SNP的A等位基因携带者。我们将研究酒精和酒精之间的潜在相互作用 通过比较吸烟和不吸烟饮酒者的尼古丁含量。为了更好地理解两者之间的机械联系 CHRNA5和酒精反应，我们将在转基因中进行行为和功能研究 表达α5基因变异体或α5零突变的动物。类似于人体研究，我们将研究 尼古丁幼稚的动物与尼古丁处理的动物的酒精自我给药。此外，我们将研究如何 CHRNA5基因变异通过测量乙醇诱导的多巴胺能系统影响酒精对多巴胺能系统的影响 电生理反应和多巴胺释放。 研究CHRNA5变异在酒精反应中的作用将提供更多的了解 酒精的神经生物学基础上的胆碱能机制，目的是提供一个扩展的 酒精奖赏反应表型的病因谱。

Alcohol use disorder (AUD) is the third leading cause of preventable death in the United States. This disease has a negative impact on health, work, and relationships of the affected individuals. Research on the genetic and environmental determinants of the response to alcohol, and their relationship to the risk of developing AUD is critical to reducing the substantial societal burden of AUD. Genetic studies have shown association of AUD with gene variation in several loci. However, due to the heterogeneity in the AUD clinical phenotype and small effect sizes, there has been an increasing interest in examining the influence of gene variation on quantitative endophenotypes such as alcohol seeking, consumption, and brain circuit alterations. The present application focuses on the potential influence of gene variation in CHRNA5, the gene encoding the α5 subunit of nicotinic acetylcholine receptors, on alcohol self-administration and brain circuit alterations. The rs16969968 missense single-nucleotide polymorphism (SNP) in CHRNA5 is associated with nicotine addiction and smoking-related consequences. However, despite the widely prevalent co-abuse of tobacco and alcohol, little work has been done to examine the effect of this SNP on alcohol use, dependence, or alcohol response. The goal of this proposal is to examine the influence of CHRNA5 variation on alcohol responses using an integrated translational pharmacogenetic approach that leverages the expertise of investigators at the NIAAA and NIDA intramural programs with the project PI to combine clinical research on human subjects and pre-clinical analyses in rodent models. A prospective study will compare alcohol self- administration behavior and neuroimaging responses in humans that are homozygous for the G-allele and those that are A-allele carriers of the CHRNA5 rs16969968 SNP. We will study the potential interaction of alcohol and nicotine by comparing smoking and non-smoking drinkers. To better understand the mechanistic link between CHRNA5 and alcohol response, we will conduct behavioral and functional studies in genetically modified animals expressing the α5 gene variants or an α5 null mutation. Similar to the human studies, we will study alcohol self-administration in nicotine-naïve vs. nicotine-treated animals. Furthermore, we will study how CHRNA5 variation influences the effects of alcohol on the dopaminergic system by measuring ethanol-induced electrophysiological responses and dopamine release. Examination of the role of CHRNA5 variation in alcohol response will provide a greater understanding of the cholinergic mechanisms underlying the neurobiology of alcohol, with the goal of providing an expanded etiological spectrum for alcohol reward response phenotypes.