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Because [GABA.sub.A] receptors containing [alpha]2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with [alpha]2 gene deletion showed reduced synaptic [GABA.sub.A] receptor-mediated responses. Behaviorally, the deletion abolished cocaine's ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of [alpha]2-[GABA.sub.A] receptors ([alpha]2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 154513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In [alpha]2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated Iocomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of [alpha]2-[GABA.sub.A] receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction. GABRA2 | behavioral sensitization | nucleus accumbens | mutant mouse | human genetics doi/10.1073/pnas.0910117107