PROJECT SUMMARY SENSITIZATION (PROJECT 2) Most people who use cocaine do not go on to develop a cocaine use disorder (CUD) suggesting that individual differences drive susceptibility to addiction. The progression from initial drug use to drug dependence is driven, in part, by genetic differences but there remain significant gaps in our knowledge of the genetic and biological etiologies underlying CUD. Individual differences in behavioral and neurobiological changes that occur in response to repeated drug exposure have been associated with CUD risk. In rodents, repeated psychostimulant exposure progressively augments locomotor activation – a phenomenon referred to as behavioral or psychomotor sensitization. Repeated exposure to drugs of abuse that yields psychomotor sensitization also alters the reward circuitry and results in hypersensitivity to the incentive motivational effects of drugs and drug- associated stimuli (incentive sensitization). Although psychomotor sensitization is often used as an indirect measure of underlying neuroadaptations, direct comparisons between individual variation in psychomotor sensitization and incentive sensitization have not been reported. The overall objective of Project 2 is to identify neurogenetic mechanisms contributing to individual differences in cocaine sensitization that may be relevant to patterns of drug use. Using our high-throughput screening regimen for behavioral sensitization developed over the current funding period, and implemented in the Behavioral Phenotyping Core, we found significant phenotypic variation in behavioral sensitization across 50 Collaborative Cross (CC) strains. We also identified CC strains with extreme phenotypes in cocaine-induced locomotor sensitivity and demonstrated that these strains exhibit divergent phenotypes in cocaine self-administration (Project 3). In this renewal, our research goals will be achieved with the following three aims: 1) To establish the relationship between behavioral and incentive sensitization in CC strains. In collaboration with the Behavioral Phenotyping Core, we will measure incentive sensitization in the same 50 CC strains. These studies will enable us to understand how strain variation in behavioral sensitization relates to differences in the motivational salience of cocaine. 2) To evaluate potential mechanisms for behavioral phenotypes observed in the CC. In collaboration with the Integrated Genetics and Genomics Core, we will characterize CC strains with extreme phenotypes to identify biological mechanisms that contribute to behavioral differences. 3) To validate candidate genes by studying behavioral sensitization and other CSNA behaviors in genetically engineered mouse models. In collaboration with the Mouse Resources and Validation Core, we will engineer overexpression and knockout models of Eed to test the role of this candidate gene in behavioral sensitization. We will also continue mapping efforts using our Diversity Outbred (DO) phenoty...