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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、工作和人际关系产生负面影响。研究对酒精反应的遗传和环境决定因素，以及它们与发展AUD对于减少AUD的重大社会负担至关重要。遗传学研究表明 AUD与几个位点的基因变异相关。然而，由于AUD临床的异质性，表型和小效应大小，人们越来越感兴趣的是检查基因的影响，定量内表型的变化，如酒精寻求，消费和脑回路改变。本申请集中于CHRNA 5中基因变异的潜在影响，编码烟碱型乙酰胆碱受体α5亚单位，对酒精自我给药和脑回路的影响改变。CHRNA 5中rs 16969968错义单核苷酸多态性（SNP）与尼古丁成瘾和吸烟相关的后果。然而，尽管广泛流行的共同滥用，烟草和酒精，很少有工作已经做了检查这种SNP对酒精使用，依赖，或酒精反应这项提案的目的是研究CHRNA 5变异对酒精的影响。使用整合的转化药物遗传学方法，利用 NIAAA和NIDA内部项目的研究人员与PI项目一起联合收割机临床研究，人类受试者和啮齿动物模型中的临床前分析。一项前瞻性研究将比较酒精自我- G-等位基因纯合子的人和那些 CHRNA 5 rs 16969968 SNP的A等位基因携带者。我们将研究酒精和通过比较吸烟和不吸烟的饮酒者。为了更好地理解 CHRNA 5和酒精反应，我们将在转基因小鼠中进行行为和功能研究。表达α5基因变体或α5无效突变的动物。与人类研究类似，我们将研究尼古丁初治动物与尼古丁给药动物的酒精自我给药。此外，我们将研究如何 CHRNA 5变异通过测量乙醇诱导的多巴胺能系统影响乙醇的作用电生理反应和多巴胺释放。研究CHRNA 5变异在酒精反应中的作用将使我们更好地理解酒精神经生物学的胆碱能机制，目的是提供一个扩展的酒精奖励反应表型的病因谱。

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.