PROJECT SUMMARY PROJECT 2 ? COCAINE SENSITIVITY AND SENSITIZATION Addiction is a chronic, relapsing disease that begins with initial exposure, followed by escalating and uncontrolled use of the drug. However, not every individual who is exposed to drugs will develop addiction. In humans, initial sensitivity to psychostimulants has been shown to predict subsequent chronic drug use, and neuroadaptations following repeated use are thought to contribute to drug craving and risk of relapse. Acute locomotor activation and chronic locomotor sensitization to psychostimulants have been developed as animal models of initial sensitivity and neuroadaptive changes. Individual differences in these behaviors have been shown to be due, in part, to genetic differences. However, identifying specific genes has been a challenge using existing animal models. This Project utilizes two new mouse populations that have been designed to study complex traits, the Collaborative Cross (CC) and Diversity Outcross (DO). These populations have increased genetic and phenotypic variability and recombination that results in more precise mapping. Using a combination of behavioral phenotyping and gene expression analysis, the CC and DO will be used to identify genes and gene networks that contribute to phenotypic variation for both acute locomotor sensitivity and sensitization. CC lines that exhibit extreme phenotypes will be further characterized to determine whether pharmacokinetic variation is responsible for behavioral differences, or whether cocaine sensitivity correlates with dendritic spine density in the nucleus accumbens. The CSNA brings together a team of scientists with expertise in various aspects of addiction-related behavior, and a common goal ? identifying the underlying genetics of addiction-related phenotypes and advancing our understanding of the shared genetic etiology that underlies specific processes of addiction. Using an integrative experimental platform we will be able to uncover the biological basis of the relationship between initial drug response, sensitization, neuroadaptation and addiction related behaviors.