Genetic mapping in collaborative cross mouse strains identifies loci that affect initial sensitivity to cocaine

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RATIONALE: Cocaine use disorder (CUD) is a significant health concern that has devastating impacts on affected individuals and society. There are currently no approved therapies to treat CUD due, in part, to significant gaps in our knowledge about the underlying factors that increase risk. Individual genetic differences contribute to CUD risk. Identifying specific genetic mechanisms that increase risk could reveal novel targets for treatment and prevention. OBJECTIVES: We identified two Collaborative Cross (CC) strains, CC004/TauUncJ (CC004) and CC041/TauUncJ (CC041), that differ significantly for locomotor response and self-administration of cocaine. In the current study, we used mapping crosses generated from both strains to identify genetic loci that are associated with behavioral responses to cocaine. RESULTS: We bred mice from the low (CC041) and high (CC004) responding strains to C57BL/6NJ mice to produce two F2 populations and identify genetic loci that influence locomotor response to cocaine. We identified three significant loci on chromosomes 7, 11 and 14 in the CC041 F2 mapping cross that collectively explain 14% of the phenotypic variance for locomotor response to cocaine. Bioinformatic analyses identified multiple genes on chromosomes 7 and 11 that are genetically plausible, have functional relevance and are suitable for further exploration. CONCLUSIONS: Genetically defined and phenotypically divergent mouse strains are a useful tool for identifying candidate genes that influence behavioral responses to psychostimulants. Functional and mechanistic analyses of these genes could provide insights into biological processes that increase risk for CUD.

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