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

Quinta, 02 Janeiro 2014 14:57

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

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

Claire I. Dixona, Hannah V. Morrisa, Gerome Breenb, Sylvane Desrivieresb, Sarah Jugurnauthb, Rebecca C. Steinera,Homero Valladab,c, Camila Guindalinib,d, Ronaldo Laranjeirad, Guilherme Messasc,d, Thomas W. Rosahle,f, John R. Atacke,
Dianne R. Pedeng, Delia Belellig, Jeremy J. Lambertg, Sarah L. Kinga, Gunter Schumannb,2, and David N. Stephensa

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. Voltageclamp 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.

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