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

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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.