Human genetic studies have linked polymorphisms in the gene encoding the GABAA receptor ?2 subunit, GABRA2, to substance abuse, but neuronal mechanism and brain regions involved are still unknown. Recent experimental evidence suggests that a global deletion of ?2-containing GABAA receptors abolishes cocaine-induced behavioral sensitization;however, it was also reported independently that during cocaine sensitization the ?2 subunit is downregulated in the nucleus accumbens. We propose to use a model system utilizing our recently developed Gabra2 floxed mouse line in which recombinant adeno- associated virus expressing cre recombinase causes a knockdown of ?2-containing GABAA receptors in the nucleus accumbens in order to evaluate whether these receptors are required for cocaine sensitization and cocaine-induced conditioned place preference. PUBLIC HEALTH RELEVANCE: genetic studies have revealed that polymorphisms in the GABRA2 gene encoding the GABAA receptor ?2 subunit are associated with substance abuse. The proposed project will investigate whether ?2-containing GABAA receptors in the nucleus accumbens are required for the the expression of addiction- related behaviors. If it is determined that ?2-containing GABAA receptors promote addiction-related behaviors, ?2-selective antagonists might be useful in the treatment of drug addiction.