Author:
Dixon Claire I.,Morris Hannah V.,Breen Gerome,Desrivieres Sylvane,Jugurnauth Sarah,Steiner Rebecca C.,Vallada Homero,Guindalini Camila,Laranjeira Ronaldo,Messas Guilherme,Rosahl Thomas W.,Atack John R.,Peden Dianne R.,Belelli Delia,Lambert Jeremy J.,King Sarah L.,Schumann Gunter,Stephens David N.
Abstract
Because GABAAreceptors 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 GABAAreceptor-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-GABAAreceptors (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−GABAAreceptors (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 theGABRA2gene to be associated with human cocaine addiction.
Publisher
Proceedings of the National Academy of Sciences
Cited by
71 articles.
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