Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors

Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors

Author Dixon, Claire I. Google Scholar
Morris, Hannah V. Google Scholar
Breen, Gerome Google Scholar
Desrivieres, Sylvane Google Scholar
Jugurnauth, Sarah Google Scholar
Steiner, Rebecca C. Google Scholar
Vallada, Homero Google Scholar
Guindalini, Camila Autor UNIFESP Google Scholar
Laranjeira, Ronaldo Autor UNIFESP Google Scholar
Messas, Guilherme Autor UNIFESP Google Scholar
Rosahl, Thomas W. Google Scholar
Atack, John R. Google Scholar
Peden, Dianne R. Google Scholar
Belelli, Delia Google Scholar
Lambert, Jeremy J. Google Scholar
King, Sarah L. Google Scholar
Schumann, Gunter Google Scholar
Stephens, David N. Google Scholar
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
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 Medical Research Council: G0600874
Medical Research Council: G0802715
European Community (EC): PL037286
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
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000274296300087

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