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

doi:10.1073/pnas.0910117107

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

Research output: Contribution to journal › Article › peer-review

68 Citations (Scopus)

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 language	English
Pages (from-to)	2289 - 2294
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	5
Early online date	19 Jan 2010
DOIs	https://doi.org/10.1073/pnas.0910117107
Publication status	Published - 2 Feb 2010

Keywords

GABRA2
behavioral sensitization
nucleus accumbens
mutant mouse
human genetics

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10.1073/pnas.0910117107

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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. (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, 107(5), 2289 - 2294. https://doi.org/10.1073/pnas.0910117107

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

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",

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",

month = feb,

day = "2",

doi = "10.1073/pnas.0910117107",

language = "English",

volume = "107",

pages = "2289 -- 2294",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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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 et al.
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 journal › Article › peer-review

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

Y1 - 2010/2/2

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.

KW - GABRA2

KW - behavioral sensitization

KW - nucleus accumbens

KW - mutant mouse

KW - human genetics

U2 - 10.1073/pnas.0910117107

DO - 10.1073/pnas.0910117107

M3 - Article

SN - 1091-6490

VL - 107

SP - 2289

EP - 2294

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 5

ER -

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

Abstract

Keywords

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