Twin studies suggest that approximately 50% of the vulnerability to cocaine use disorder is determined by genetic factors, but genome-wide association studies (GWAS) in humans have only begun to identify specific genes that confer this risk. One major impediment to studies of cocaine use disorder is the complexity of the phenotype and the lack of control of environmental variables. We propose a complementary approach that leverages a multidisciplinary, highly collaborative consortium 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 cocaine use by performing a GWAS in N/NIH heterogeneous stock rats. We will use the most relevant animal model of cocaine use disorder (i.e., escalation of intravenous cocaine self-administration) and highly standardized measures of controlled and compulsive cocaine self-administration. To increase the impact of these findings and facilitate translational and basic research studies on the mechanisms underlying compulsive cocaine use, we will also establish a data/tissue repository (CocaineBioBank.org) from behaviorally and genetically characterized animals that will allow researchers to further investigate the cellular and molecular mechanisms underlying compulsive cocaine 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 cocaine use in male and female outbred rats, (2) identify genes associated with compulsive cocaine use, (3) create the CocainBioBank 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.
Updated Sept 8, 2020