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

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 and Howard C. Thomas
Additional contact information
Quentin M. Anstee: Institute of Cellular Medicine, The Medical School, Newcastle University
Susanne Knapp: Mammalian Genetics Unit, MRC Harwell
Edward P. Maguire: Medical Research Institute, University of Dundee, Ninewells Hospital
Alastair M. Hosie: Physiology and Pharmacology, University College London
Philip Thomas: Physiology and Pharmacology, University College London
Martin Mortensen: Physiology and Pharmacology, University College London
Rohan Bhome: Physiology and Pharmacology, University College London
Alonso Martinez: Imperial College, St Mary’s Hospital Campus
Sophie E. Walker: School of Psychology, University of Sussex
Claire I. Dixon: School of Psychology, University of Sussex
Kush Ruparelia: UCL Institute for Liver and Digestive Health, Royal Free Campus, University College London Medical School
Sara Montagnese: UCL Institute for Liver and Digestive Health, Royal Free Campus, University College London Medical School
Yu-Ting Kuo: MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Amy Herlihy: MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Jimmy D. Bell: MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Iain Robinson: National Institute for Medical Research
Irene Guerrini: Molecular Psychiatry Laboratory, Royal Free and University College London Medical School, Windeyer Institute of Medical Sciences
Andrew McQuillin: Molecular Psychiatry Laboratory, Royal Free and University College London Medical School, Windeyer Institute of Medical Sciences
Elizabeth M.C. Fisher: Institute of Neurology, University College London
Mark A. Ungless: MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
Hugh M.D. Gurling: Molecular Psychiatry Laboratory, Royal Free and University College London Medical School, Windeyer Institute of Medical Sciences
Marsha Y. Morgan: UCL Institute for Liver and Digestive Health, Royal Free Campus, University College London Medical School
Steve D.M. Brown: Mammalian Genetics Unit, MRC Harwell
David N. Stephens: School of Psychology, University of Sussex
Delia Belelli: Medical Research Institute, University of Dundee, Ninewells Hospital
Jeremy J. Lambert: Medical Research Institute, University of Dundee, Ninewells Hospital
Trevor G. Smart: Physiology and Pharmacology, University College London
Howard C. Thomas: Mammalian Genetics Unit, MRC Harwell

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: 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.

Date: 2013
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms3816 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3816

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms3816

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().