Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors
| Autor: | Sylvane Desrivières, Gerome Breen, Thomas W. Rosahl, H.V. Morris, Camila Guindalini, Rebecca C. Steiner, Jeremy J. Lambert, Gunter Schumann, Dianne R. Peden, John R. Atack, Guilherme Peres Messas, David N. Stephens, Sarah L. King, Homero Vallada, Delia Belelli, Sarah Jugurnauth, Ronaldo Laranjeira, Claire I. Dixon |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Azides media_common.quotation_subject Dopamine Nucleus accumbens Pharmacology Biology Medium spiny neuron Amygdala Polymorphism Single Nucleotide Nucleus Accumbens 03 medical and health sciences Benzodiazepines Cocaine-Related Disorders Mice Young Adult 0302 clinical medicine Cocaine Reward Conditioning Psychological medicine Animals Humans Learning Point Mutation GABRA2 Receptor 030304 developmental biology media_common Mice Knockout 0303 health sciences Multidisciplinary Binding Sites GABAA receptor Addiction Biological Sciences Receptors GABA-A Mice Mutant Strains Mice Inbred C57BL medicine.anatomical_structure nervous system Case-Control Studies biology.protein Female 030217 neurology & neurosurgery medicine.drug |
| Popis: | Because GABA A 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 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 α2-GABA A 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−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. |
| Databáze: | OpenAIRE |
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