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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：
10413132
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/10413132
关键词：
Acute Address Affect Alcohol consumption Alcohols Alleles Animals Area Attention Behavior Behavioral Brain Chronic Disease Clinical Research Cognitive Complement Consumption Corpus striatum structure Cues Dependence Disease Dopamine Dopaminergic Cell Drosophila acetylcholine receptor alpha-subunit Electrophysiology (science)Ethanol Etiology Food Functional Magnetic Resonance Imaging Functional disorder Genes Genetic Genetic Polymorphism Genetic study Genetically Modified Animals Genotype Goals Health Heterogeneity Human Incentives Individual Intramural Research Program Intravenous Laboratories Link 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 comorbidity conditioned place preference dopamine system dopaminergic neuron drinking endophenotype experimental study flexibility functional MRI scan genetic linkage genetic variant hedonic human subject in vivo incentive salience interest neural correlate neuroimaging non-smoking null mutation pre-clinical 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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutation of the α5 nicotinic acetylcholine receptor subunit increases ethanol and nicotine consumption in adolescence and impacts adult drug consumption.

DOI：
10.1016/j.neuropharm.2022.109170
发表时间：
2022-09-15
期刊：
NEUROPHARMACOLOGY
影响因子：
4.7
作者：
Quijano Carde, Natalia A;Shaw, Jessica;Carter, Christina;Kim, Seung;Stitzel, Jerry A;Venkatesh, Shyamala K;Ramchandani, Vijay A;De Biasi, Mariella
通讯作者：
De Biasi, Mariella

Behavioral characterization of withdrawal following chronic voluntary ethanol consumption via intermittent two-bottle choice points to different susceptibility categories.