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

Anstee, Quentin M., Knapp, Susanne, Maguire, Edward P., Hosie, Alastair M., Thomas, Philip, Mortensen, Martin, Bhome, Rohan, Martinez, Alonso, Walker, Sophie E., Dixon, Claire I., Ruparelia, Kush, Montagnese, Sara, Kuo, Yu-Ting, Herlihy, Amy, Bell, Jimmy D., Robinson, Iain, Guerrini, Irene, McQuillin, Andrew, Fisher, Elizabeth M.C., Ungless, Mark A., Gurling, Hugh M.D., Morgan, Marsha Y., Brown, Steve D.M., Stephens, David N., Belelli, Delia, Lambert, Jeremy J., Smart, Trevor G. and Thomas, Howard C. (2013) Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition. Nature Communications, 4. p. 2816. ISSN 2041-1723

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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 γ-aminobutyric acidA receptor (GABAAR) β1 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.

Item Type: Article
Schools and Departments: School of Psychology > Psychology
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry
Depositing User: Chris Keene
Date Deposited: 27 Nov 2013 09:12
Last Modified: 27 Nov 2013 09:12
URI: http://sro.sussex.ac.uk/id/eprint/47152
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