Translational study on CHRNA5 variation and alcohol reward mechanisms

CHRNA5变异与酒精奖励机制的转化研究

基本信息

批准号：
9521693
负责人：
Mariella De Biasi
金额：
$ 36.23万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-20 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9521693
关键词：
Acute Address Affect Alcohol consumption Alcohols Alleles Animals Area Attention Behavior Behavioral Brain Chronic Disease Clinical Research Cognitive Comorbidity Complement Consumption Corpus striatum structure Cues Dependence Disease Dopamine Dopaminergic Cell Drosophila acetylcholine receptor alpha-subunit Duct (organ) structure Electrophysiology (science)Ethanol Etiology Food Functional Magnetic Resonance Imaging Functional disorder Gene Targeting Genes Genetic Genetic Polymorphism Genetic study Genetically Modified Animals Genotype Goals Health Heterogeneity Human Incentives Individual Intramural Research Program Intravenous Laboratories Link MRI Scans Measures Mediating Microdialysis Modeling Mus National Institute of Drug Abuse National Institute on Alcohol Abuse and Alcoholism Neurobiology Neurons Nicotine Nicotine Dependence Nicotinic Receptors Nucleus Accumbens Participant Patient Recruitments Pennsylvania Pharmacogenetics Phenotype Play Pre-Clinical Model Property Prospective Studies Psychological reinforcement Recording of previous events Research Research Personnel Rest Reversal Learning Rewards Risk Rodent Model Role Scanning Self Administration Signal Transduction Single Nucleotide Polymorphism Slice Smoking System Tobacco Transgenic Mice United States United States National Institutes of Health Universities Variant Ventral Tegmental Area Wild Type Mouse Work addiction alcohol behavior alcohol effect alcohol exposure alcohol reinforcement alcohol response alcohol reward alcohol seeking behavior alcohol use disorder base burden of illness cholinergic clinical phenotype dopamine system dopaminergic neuron drinking endophenotype experimental study flexibility genetic linkage genetic variant hedonic human subject in vivo incentive salience interest neural correlate neuroimaging non-smoking null mutation pre-clinical preference preventable death public health relevance relating to nervous system response selective expression sex skills tobacco abuse trait translational study virtual

项目摘要

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.

酒精使用障碍（AUD）是美国可预防死亡的第三主要原因。这疾病对受影响个体的健康，工作和关系产生负面影响。研究对酒精反应的遗传和环境决定者及其与风险的关系开发AUD对于减少AUD的大量社会燃烧至关重要。遗传研究表明 AUD与几个地方基因变异的关联。但是，由于AUD临床的异质性表型和小效应大小，在检查基因的影响方面越来越兴趣定量内表型的变化，例如寻求酒精，消费和脑电路改变。本应用的重点是基因基因的潜在影响，基因编码烟碱乙酰胆碱受体的α5亚基，关于酒精的自我给药和脑电路改变。 CHRNA5中的RS16969968单核苷酸多态性（SNP）与CHRNA5相关尼古丁成瘾和与吸烟有关的后果。然而，尽管普遍存在烟草和酒精，几乎没有完成研究SNP对酒精使用，依赖性或酒精反应。该提案的目的是检查CHRNA5变异对酒精的影响使用集成翻译的药物遗传学方法的反应，该方法利用了专家 NIAAA和NIDA壁内计划的研究人员与PI项目相结合了有关的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自我对G贵族纯合的人类的行政行为和神经影像反应是Chrna5 rs16969968 SNP的A-Allele载体。我们将研究酒精的潜在相互作用尼古丁通过比较吸烟和不吸烟的饮酒者。更好地了解 CHRNA5和酒精反应，我们将在基因修改中进行行为和功能研究表达α5基因变异或α5无效突变的动物。与人类研究类似，我们将研究酒精在尼古丁与尼古丁处理的动物中的自我管理。此外，我们将研究 CHRNA5的变异通过测量乙醇诱导的电生理反应和多巴胺释放。检查CHRNA5变异在酒精反应中的作用将提供更多了解酒精神经生物学基础的胆碱能机制，目的是提供扩展酒精奖励反应表型的病因谱。