Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition

Quentin Anstee; Susanne Knapp; Edward P. Maguire; Alastair M. Hosie; Philip Thomas; Martin Mortensen; Rohan Bhome; Alonso Martinez; Sophie E. Walker; Claire I. Dixon; Kush Ruparelia; Sara Montagnese; Yu-Ting Kuo; Amy Herlihy; Jimmy D. Bell; Iain Robinson; Irene Guerrini; Andrew McQuillin; Elizabeth M.C. Fisher; Mark A. Ungless; Hugh M. D. Gurling; Marsha Y. Morgan; Steve D.M. Brown; David N. Stephens; Delia Belelli; Jeremy Lambert; Trevor G. Smart; Howard C. Thomas

doi:10.1038/ncomms3816

Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition

Quentin Anstee, Susanne Knapp, Edward P. Maguire, Alastair M. Hosie, Philip Thomas, Martin Mortensen, Rohan Bhome, Alonso Martinez, Sophie E. Walker, Claire I. Dixon, Kush Ruparelia, Sara Montagnese, Yu-Ting Kuo, Amy Herlihy, Jimmy D. Bell, Iain Robinson, Irene Guerrini, Andrew McQuillin, Elizabeth M.C. Fisher, Mark A. UnglessHugh M. D. Gurling, Marsha Y. Morgan, Steve D.M. Brown, David N. Stephens, Delia Belelli, Jeremy Lambert, Trevor G. Smart, Howard C. Thomas

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Abstract

Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the g-aminobutyric acidA receptor (GABAAR) b1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse.

Original language	English
Article number	2816
Journal	Nature Communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3816
Publication status	Published - 26 Nov 2013

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Anstee, Q., Knapp, S., Maguire, E. P., Hosie, A. M., Thomas, P., Mortensen, M., Bhome, R., Martinez, A., Walker, S. E., Dixon, C. I., Ruparelia, K., Montagnese, S., Kuo, Y.-T., Herlihy, A., Bell, J. D., Robinson, I., Guerrini, I., McQuillin, A., Fisher, E. M. C., ... Thomas, H. C. (2013). Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition. Nature Communications, 4, Article 2816. https://doi.org/10.1038/ncomms3816

@article{50066f2c0f2f40f8908d0ccfafbb1128,

title = "Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition",

abstract = "Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the g-aminobutyric acidA receptor (GABAAR) b1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse.",

author = "Quentin Anstee and Susanne Knapp and Maguire, {Edward P.} and Hosie, {Alastair M.} and Philip Thomas and Martin Mortensen and Rohan Bhome and Alonso Martinez and Walker, {Sophie E.} and Dixon, {Claire I.} and Kush Ruparelia and Sara Montagnese and Yu-Ting Kuo and Amy Herlihy and Bell, {Jimmy D.} and Iain Robinson and Irene Guerrini and Andrew McQuillin and Fisher, {Elizabeth M.C.} and Ungless, {Mark A.} and Gurling, {Hugh M. D.} and Morgan, {Marsha Y.} and Brown, {Steve D.M.} and Stephens, {David N.} and Delia Belelli and Jeremy Lambert and Smart, {Trevor G.} and Thomas, {Howard C.}",

year = "2013",

month = nov,

day = "26",

doi = "10.1038/ncomms3816",

language = "English",

volume = "4",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Anstee, Q, Knapp, S, Maguire, EP, Hosie, AM, Thomas, P, Mortensen, M, Bhome, R, Martinez, A, Walker, SE, Dixon, CI, Ruparelia, K, Montagnese, S, Kuo, Y-T, Herlihy, A, Bell, JD, Robinson, I, Guerrini, I, McQuillin, A, Fisher, EMC, Ungless, MA, Gurling, HMD, Morgan, MY, Brown, SDM, Stephens, DN, Belelli, D, Lambert, J, Smart, TG & Thomas, HC 2013, 'Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition', Nature Communications, vol. 4, 2816. https://doi.org/10.1038/ncomms3816

TY - JOUR

T1 - Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition

AU - Anstee, Quentin

AU - Knapp, Susanne

AU - Maguire, Edward P.

AU - Hosie, Alastair M.

AU - Thomas, Philip

AU - Mortensen, Martin

AU - Bhome, Rohan

AU - Martinez, Alonso

AU - Walker, Sophie E.

AU - Dixon, Claire I.

AU - Ruparelia, Kush

AU - Montagnese, Sara

AU - Kuo, Yu-Ting

AU - Herlihy, Amy

AU - Bell, Jimmy D.

AU - Robinson, Iain

AU - Guerrini, Irene

AU - McQuillin, Andrew

AU - Fisher, Elizabeth M.C.

AU - Ungless, Mark A.

AU - Gurling, Hugh M. D.

AU - Morgan, Marsha Y.

AU - Brown, Steve D.M.

AU - Stephens, David N.

AU - Belelli, Delia

AU - Lambert, Jeremy

AU - Smart, Trevor G.

AU - Thomas, Howard C.

PY - 2013/11/26

Y1 - 2013/11/26

N2 - Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the g-aminobutyric acidA receptor (GABAAR) b1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse.

AB - Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the g-aminobutyric acidA receptor (GABAAR) b1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABAARs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABAAR function and increased alcohol consumption that could underlie some forms of alcohol abuse.

U2 - 10.1038/ncomms3816

DO - 10.1038/ncomms3816

M3 - Article

C2 - 24281383

SN - 2041-1723

VL - 4

JO - Nature Communications

JF - Nature Communications

M1 - 2816

ER -

Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition

Abstract

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