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. ![]() |
Institution | Univ Sussex Kings Coll London Universidade de São Paulo (USP) Merck Sharp & Dohme Ltd Merck Res Labs Universidade Federal de São Paulo (UNIFESP) Univ Dundee |
Abstract | 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. |
Keywords |
GABRA2
behavioral sensitization nucleus accumbens mutant mouse human genetics |
Language | English |
Sponsor | Medical Research Council European Community (EC) Tenovus and the Anonymous Trust Marie Curie Reintegration Biotechnology and Biological Sciences Research Council British Pharmacological Society Merck Sharp Dohme Wellcome Trust United Kingdom Department of Health National Institute for Health Research-Biomedical Research Centre Mental Health Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) |
Grant number |
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Date | 2010-02-02 |
Published in | Proceedings of the National Academy of Sciences of the United States of America. Washington: Natl Acad Sciences, v. 107, n. 5, p. 2289-2294, 2010. |
ISSN | 0027-8424 (Sherpa/Romeo, impact factor) |
Publisher | Natl Acad Sciences |
Extent | 2289-2294 |
Origin |
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Access rights | Open access ![]() |
Type | Article |
Web of Science ID | WOS:000274296300087 |
URI | http://repositorio.unifesp.br/handle/11600/32260 |
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