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 Council[G0600874]

Medical Research Council

Medical Research Council[G0802715]

Medical Research Council

European Community (EC)

European Community (EC)[PL037286]

Tenovus and the Anonymous Trust

Tenovus and the Anonymous Trust

Marie Curie Reintegration

Marie Curie Reintegration

Biotechnology and Biological Sciences Research Council

Biotechnology and Biological Sciences Research Council

British Pharmacological Society

British Pharmacological Society

Merck

Merck

Sharp

Sharp

Dohme

Dohme

Wellcome Trust

Wellcome Trust

United Kingdom Department of Health National Institute for Health Research-Biomedical Research Centre Mental Health

United Kingdom Department of Health National Institute for Health Research-Biomedical Research Centre Mental Health

FAPESP Sao Paulo Research Foundation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)