Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors

Because GABA(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(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(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 15-4513 (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 locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of alpha 2-GABA(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.Medical Research CouncilEuropean Community (EC)Tenovus and the Anonymous TrustMarie Curie ReintegrationBiotechnology and Biological Sciences Research CouncilBritish Pharmacological SocietyMerckSharpDohmeWellcome TrustUnited Kingdom Department of Health National Institute for Health Research-Biomedical Research Centre Mental HealthFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ Sussex, Dept Psychol, Brighton BN1 9QG, E Sussex, EnglandKings Coll London, Inst Psychiat, MRC, Social Genet & Dev Psychiat Ctr, London SE5 8AF, EnglandUniv São Paulo, Inst Psychiat, BR-05508900 São Paulo, BrazilMerck Sharp & Dohme Ltd, Neurosci Res Ctr, Harlow CM20 2QR, Essex, EnglandMerck Res Labs, Rahway, NJ USAUniversidade Federal de São Paulo, BR-04023900 São Paulo, BrazilUniv Dundee, Ctr Neurosci, Dundee DD1 9SY, ScotlandUniversidade Federal de São Paulo, BR-04023900 São Paulo, BrazilMedical Research Council: G0600874Medical Research Council: G0802715European Community (EC): PL037286Web of Scienc