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

Author

Listed:
  • Quentin M. Anstee

    (Institute of Cellular Medicine, The Medical School, Newcastle University
    Mammalian Genetics Unit, MRC Harwell
    Imperial College, St Mary’s Hospital Campus)

  • Susanne Knapp

    (Mammalian Genetics Unit, MRC Harwell
    Imperial College, St Mary’s Hospital Campus)

  • 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
    Present address: Cancer Genetic Group, Infection and Cancer, Department Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellin, Colombia)

  • 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
    Present address: Department of Medicine, via Giustiniani, 2, 35128 Padova, Italy)

  • Yu-Ting Kuo

    (MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital
    Present address: Department of Medical Imaging, Chi Mei Medical Center, Tainan City, Taiwan)

  • 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
    Imperial College, St Mary’s Hospital Campus)

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.

Suggested Citation

  • 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 & Sar, 2013. "Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3816
    DOI: 10.1038/ncomms3816
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