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

Claire I. Dixon, Hannah V. Morris, Gerome Breen, Sylvane Desrivieres, Sarah Jugurnauth, Rebecca C. Steiner, Homero Vallada, Camila Guindalini, Ronaldo Laranjeira, Guilherme Messas, Thomas W. Rosahl, John R. Atack, Dianne R. Peden, Delia Belelli, Jeremy J. Lambert, Sarah L. King, Gunter Schumann, David N. Stephens (Lead / Corresponding author)

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    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.

    Original languageEnglish
    Pages (from-to)2289-2294
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number5
    DOIs
    Publication statusPublished - 2 Feb 2010

    Keywords

    • GABRA2
    • behavioral sensitization
    • nucleus accumbens
    • mutant mouse
    • human genetics
    • KNOCK-OUT MICE
    • BEHAVIORAL SENSITIZATION
    • ALCOHOL DEPENDENCE
    • NUCLEUS-ACCUMBENS
    • ADULT-RAT
    • REINFORCEMENT
    • AMYGDALA
    • REWARD
    • BRAIN

    Cite this

    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. / Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 5. pp. 2289-2294.
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    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.",
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    author = "Dixon, {Claire I.} and Morris, {Hannah V.} and Gerome Breen and Sylvane Desrivieres and Sarah Jugurnauth and Steiner, {Rebecca C.} and Homero Vallada and Camila Guindalini and Ronaldo Laranjeira and Guilherme Messas and Rosahl, {Thomas W.} and Atack, {John R.} and Peden, {Dianne R.} and Delia Belelli and Lambert, {Jeremy J.} and King, {Sarah L.} and Gunter Schumann and Stephens, {David N.}",
    year = "2010",
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    Dixon, CI, Morris, HV, Breen, G, Desrivieres, S, Jugurnauth, S, Steiner, RC, Vallada, H, Guindalini, C, Laranjeira, R, Messas, G, Rosahl, TW, Atack, JR, Peden, DR, Belelli, D, Lambert, JJ, King, SL, Schumann, G & Stephens, DN 2010, 'Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 5, pp. 2289-2294. https://doi.org/10.1073/pnas.0910117107

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

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 5, 02.02.2010, p. 2289-2294.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Cocaine effects on mouse incentive-learning and human addiction are linked to alpha 2 subunit-containing GABA(A) receptors

    AU - Dixon, Claire I.

    AU - Morris, Hannah V.

    AU - Breen, Gerome

    AU - Desrivieres, Sylvane

    AU - Jugurnauth, Sarah

    AU - Steiner, Rebecca C.

    AU - Vallada, Homero

    AU - Guindalini, Camila

    AU - Laranjeira, Ronaldo

    AU - Messas, Guilherme

    AU - Rosahl, Thomas W.

    AU - Atack, John R.

    AU - Peden, Dianne R.

    AU - Belelli, Delia

    AU - Lambert, Jeremy J.

    AU - King, Sarah L.

    AU - Schumann, Gunter

    AU - Stephens, David N.

    PY - 2010/2/2

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    N2 - 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.

    AB - 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.

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    KW - nucleus accumbens

    KW - mutant mouse

    KW - human genetics

    KW - KNOCK-OUT MICE

    KW - BEHAVIORAL SENSITIZATION

    KW - ALCOHOL DEPENDENCE

    KW - NUCLEUS-ACCUMBENS

    KW - ADULT-RAT

    KW - REINFORCEMENT

    KW - AMYGDALA

    KW - REWARD

    KW - BRAIN

    U2 - 10.1073/pnas.0910117107

    DO - 10.1073/pnas.0910117107

    M3 - Article

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    JF - Proceedings of the National Academy of Sciences

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