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Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors

Dixon, C. I., Morris, H. V., Breen, G., Desrivieres, S., Jugurnauth, S., Steiner, R. C., Vallada, H., Guindalini, C., Laranjeira, R., Messas, G., Rosahl, T. W., Atack, J. R., Peden, D. R., Belelli, D., Lambert, J. J., King, S. L., Schumann, G. and Stephens, D. N. 2010. Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors. Proceedings of the National Academy of Sciences 107 (5) , pp. 2289-2294. 10.1073/pnas.0910117107

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Because GABAA receptors containing α2 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 α2 gene deletion showed reduced synaptic GABAA 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 α2-GABAA receptors (α2H101R), 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 α2H101R, 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 α2−GABAA 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: National Academy of Sciences
ISSN: 1091-6490
Date of Acceptance: 17 December 2009
Last Modified: 14 Nov 2017 21:02

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