Organismal and Genetic Networks in Drug Reward and Reinforcement

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DESCRIPTION (provided by applicant): The impact of cocaine addiction on the lives of those who suffer from it, their families and society as a whole is staggering. The specific factors that determine an individuals' risk of transitioning from initial cocaine use to abuse and addiction are largely unknown but a role for genetics has been established. Therefore, identification of specific genes that increase susceptibility to abuse cocaine has been an area of considerable effort in the research community. Attempts to identify genetic loci involved in addiction liabilityin human populations have met with some success but are complicated by lack of environmental control, genetic heterogeneity, the need for large sample sizes and ethical concerns. Genetically stable mouse populations have proven useful for the study of complex human diseases like addiction. While mice will never replicate the entire spectrum of traits that define the human disease state, there are commonly used behavioral models that are believed to faithfully represent key features of addiction. Most drugs of abuse cause psychomotor stimulation when administered acutely and initial sensitivity to a drug has been associated with increased risk for subsequent use and abuse. Therefore, locomotor activation in response to cocaine is often used as a model for addiction-related behavior in mice. It has been known for some time that inbred strains of mice differ widely in their locomotor response to cocaine proving a role for genetics in this complex behavior. More recently, a dense SNP panel has been developed that allows for determination of haplotype structure in inbred mouse strains. These SNP data, along with inbred strain behavioral data, can be used to conduct genome-wide association mapping (GWAS) to identify genomic loci that are associated with cocaine locomotor response. We have recently completed a 45 inbred strain survey of cocaine-induced locomotor response and have identified multiple genetic loci that influence the behavior. The goal of this application is to replicate these QTL in standard intercross (F2) populations and use haplotype information from inbred strains to narrow QTL intervals and identify candidate genes. We also propose to test a set of candidate genes by measuring behavior in knockout lines and by complementation testing. Finally, we propose to examine inbred strains at the extreme ends of the phenotypic distribution in an attempt to uncover the biological mechanisms that contribute to initial locomotor sensitivity to cocaine and may increase risk for addiction.