Identification of Genetic Variants that Influence Compulsive Alcohol Intake in Outbred Rats

摘要 对药物滥用和上瘾的脆弱性有一个可遗传的组成部分。尤其是家庭和双胞胎研究 证明大约45%-65%的酒精使用障碍的易感性是由基因决定的 各种因素。在过去的十年里，遗传学的进步为寻找这种分子提供了关键线索。 酒精使用和滥用的依据。人类全基因组关联研究(GWAS)已得到扩展 巨大的规模和复杂程度，导致数百个基因与一系列酒精有关- 相关特征。酒精使用障碍研究的一个主要障碍是表型和 缺乏对环境变量的控制。我们提出了一种互补和多学科的方法 将下一代测序与最先进的行为筛查相结合，在一种独特的、遗传的 多样化的非人类动物模型。这项提议的主要目标是识别出 与强制性饮酒、耐受性和对FDA批准的反应增加相关 对N/NIH异种系大鼠进行GWA给药。我们将使用最相关的动物 酒精使用障碍的模型(即在慢性间歇性接触酒精蒸气后升级)和高度 规范的强制饮酒自我管理措施与纵向评估相结合 撤退的迹象。增加这些发现的影响并促进翻译和基础研究 关于强迫饮酒的机制的研究，我们还将建立一个数据/组织存储库 来自行为和基因特征的动物，将使研究人员能够进一步研究 强迫性酒精使用的细胞和分子机制及其生物学变化 与特定基因变异体的表达有关。这个项目很可能会有一个持续和强大的 对该领域的影响，因为它将(1)表征从受控饮酒到强制饮酒的转变 雄性和雌性近交系大鼠，(2)识别与强迫饮酒相关的基因和反应 对于目前FDA批准的药物，(3)创建酒精生物库，该库将提供免费访问 脑、肾、肝、脾、卵巢、睾丸、肾上腺和血液标本用各种组织保存 方案将允许产生诱导的多能干细胞以及神经解剖学，分子， 对具有行为/遗传特征的动物进行生化和药理学研究。

Abstract Vulnerability to substance abuse and addiction has a heritable component. In particular, family and twin studies demonstrate that about 45-65% of the vulnerability to develop alcohol use disorder is determined by genetic factors. In the past decade, advances in genetics have provided critical clues in the search for the molecular basis of alcohol use and abuse. Human genome-wide association studies (GWAS) have expanded dramatically in size and sophistication, which has led to hundreds of loci being implicated in a range of alcohol- related traits. One major impediment to studies of alcohol use disorder is the complexity of the phenotype and the lack of control of environmental variables. We propose a complementary and multidisciplinary approach that combines next-generation sequencing with state-of-the-art behavioral screening in a unique, genetically diverse, nonhuman animal model. The primary goal of this proposal is to identify gene variants that are associated with increased vulnerability to compulsive alcohol use, tolerance and response to FDA approved medications by performing a GWAS in N/NIH heterogeneous stock rats. We will use the most relevant animal model of alcohol use disorder (i.e., escalation after chronic intermittent access to alcohol vapor) and highly standardized measures of compulsive alcohol self-administration combined with longitudinal assessment of withdrawal signs. To increase the impact of these findings and facilitate translational and basic research studies on the mechanisms underlying compulsive alcohol use, we will also establish a data/tissue repository from behaviorally and genetically characterized animals that will allow researchers to further investigate the cellular and molecular mechanisms underlying compulsive alcohol use and identify the biological changes associated with the expression of specific gene variants. This project is likely to have a sustained and powerful impact on the field because it will (1) characterize the transition from controlled to compulsive alcohol use in male and female outbred rats, (2) identify genes associated with compulsive alcohol use and the the response to the currently FDA approved medications , (3) create the Alcohol BioBank which will provide free access to brain, kidney, liver, spleen, ovary, testis, adrenal, and blood samples with a variety of tissue preservation protocols that will allow the generation of induced pluripotent stem cells as well as neuroanatomical, molecular, biochemical, and pharmacological studies on behaviorally/genetically characterized animals.