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Cited by 77Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchNicotinic Acetylcholine Receptors Study

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

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Dixon, Claire I., Morris, Hannah V., Breen, Gerome, Desrivieres, Sylvane, Jugurnauth, Sarah, Steiner, Rebecca C., Vallada, Homero, Guindalini, Camila +10 more·2010·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0910117107PMC PMC2836671
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Abstract

Because GABA(A) receptors containing alpha2 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 alpha2 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 alpha2-GABA(A) receptors (alpha2H101R), 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 alpha2H101R, 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 alpha2-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.

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  • GABAARs in brain reward circuits may be involved in the development of brain changes that mediate the addictive properties of drugs in general.

    “The involvement of GABAAR genes in the abuse of and dependence on drugs that do not directly affect the GABAARs suggest that the GABAARs in brain reward circuits may be involved in the development of brain changes that mediate the addictive properties of drugs in general.”

    From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [99]

  • NAc α2GABAARs are required for the development of behavioral sensitization to cocaine.

    “A reduction in NAc α2GABAARs accompanies cocaine sensitization through long-term administration [120], while there is some evidence that these same receptors are required for the development of behavioral sensitization to cocaine in the first place [99,121], which may explain both initial sensitization and later acceleration of intake.”

    From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [99]

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Authors
Dixon, C. I., Morris, H. V., Breen, G., Desrivieres, S., Jugurnauth, S., Steiner, R. C., Vallada, H., Guindalini, C., Laranjeira, R., Messas, G., Rosahl, T. W., Atack, J. R., Peden, D. R., Belelli, D., Lambert, J. J., King, S. L., Schumann, G., & Stephens, D. N.
Affiliations
  • University of Sussex (GB)
  • King's College London (GB)
  • Medical Research Council–Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College, London SE5 8AF, United Kingdom;
  • Universidade de São Paulo (BR)
  • Universidade Federal de São Paulo (BR)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • MSD (UK) Limited (United Kingdom) (GB)
  • University of Dundee (GB)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2010-01-19
Volume
107
Issue
5
Pages
2289-2294
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0910117107
PMC
PMC2836671
OpenAlex
W2021553637
Cited by
77
References
36
Citations by year
2025: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 8 · 2015: 4 · 2014: 12 · 2013: 8 · 2012: 12
FWCI
3.36
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
  • Americanae (AECID Library) (submittedVersion, other-oa)
  • Discovery Research Portal (University of Dundee) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Funders
Wellcome Trust
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
cocaine, GABRA2, nucleus accumbens, medium spiny neurons, incentive learning, conditioned reinforcement, behavioral sensitization, benzodiazepine binding, Ro 15-4513, cocaine dependence, GABAergic neurotransmission, motivation and reward
MeSH terms
Adult, Animals, Azides, Benzodiazepines, Binding Sites, Cocaine, Conditioning, Psychological, Dopamine, Female, Humans, Learning, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Nucleus Accumbens, Receptors, GABA-A, Reward, Case-Control Studies, Point Mutation, Mice, Knockout, Cocaine-Related Disorders, Polymorphism, Single Nucleotide, Mice, Young Adult

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