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

2013; Nature Portfolio; Volume: 4; Issue: 1 Linguagem: Inglês

10.1038/ncomms3816

2041-1723

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

GABA and Rice Research

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. Mutations in the GABA A receptor have been implicated in alcohol dependence in humans. In this study, the authors show that mice with mutations in the beta 1 subunit of the GABA A receptor exhibit spontaneous GABA A channel opening and preferentially consume alcohol, working harder to access it.