PROJECT SUMMARY Over the past 5-10 years, the opioid epidemic has become a national crisis in the United States. Currently, few good treatment options exist, and little is known about the underlying mechanisms contributing to risk for addiction and to drug effects on the brain. This project addresses both of these issues using a rat genetic model to identify genetic contributions to phenotypes associated with the development of opioid use disorders. We will identify oxycodone-related phenotypic, genotypic, and RNA expression differences within the HXB/BXH RI strains and 15 additional inbred rat strains for which genetic data are available, drawn from the Hybrid Rat Diversity Panel (HRDP). Our preliminary phenotypic data suggest that the founder strains SHR/OlaIpcv and BN-Lx/Cub, along with the ACI strain, differ on many of the phenotypic traits assessed including the self-administration of oxycodone. In Aim 1, 48 inbred rat strains will be assessed for multiple oxycodone-related behavioral phenotypes, including measures of analgesia. Quantitative trait loci (QTL) associated with these behaviors will be identified using existing genetic data. In Aim 2, we will perform RNA sequencing using tissue from the nucleus accumbens and amygdala in naïve animals and in rats following oxycodone self-administration. This will identify genes that differ by strain, which will be informative about baseline risk by genotype, and also identify genes that differ in response to oxycodone (shared and unshared across strains). Because genes do not operate independently, but work in networks and pathways, Aim 3 will employ a systems genetics approach to identify genetic networks involved in baseline differences across strains and in the response to oxycodone self-administration. Across all aims, we will compare the QTL regions, RNA expression differences, and gene network pathways to those found by others in the field using complementary rodent models and/or human studies (including our collaborator Dr. Olivier George) in order to narrow focus on priority genes and pathways.