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.