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Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition
journal contribution
posted on 2023-06-08, 16:24 authored by Quentin M. 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 J. Lambert, Trevor G. Smart, Howard C. ThomasAlcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the ?-aminobutyric acidA receptor (GABAAR) ß1 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.
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Publication status
- Published
Journal
Nature CommunicationsISSN
2041-1723External DOI
Volume
4Page range
2816Department affiliated with
- Psychology Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2013-11-27Usage metrics
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