title: Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition.
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.
authors.affiliation: 1] Institute of Cellular Medicine, The Medical School, Newcastle University, 4th Floor William Leech Building, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK [2] Mammalian Genetics Unit, MRC Harwell, Oxford OX11 0RD, UK [3] Department of Gastroenterology and Hepatology, Imperial College, St Mary's Hospital Campus, Praed Street, London W2 1NY, UK [4].
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.forename: Susanne
authors.initials: S
authors.lastname: Knapp
authors.forename: Edward P
authors.initials: EP
authors.lastname: Maguire
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Hosie
authors.forename: Philip
authors.initials: P
authors.lastname: Thomas
authors.forename: Martin
authors.initials: M
authors.lastname: Mortensen
authors.forename: Rohan
authors.initials: R
authors.lastname: Bhome
authors.forename: Alonso
authors.initials: A
authors.lastname: Martinez
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Walker
authors.forename: Claire I
authors.initials: CI
authors.lastname: Dixon
authors.forename: Kush
authors.initials: K
authors.lastname: Ruparelia
authors.forename: Sara
authors.initials: S
authors.lastname: Montagnese
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Kuo
authors.forename: Amy
authors.initials: A
authors.lastname: Herlihy
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Bell
authors.forename: Iain
authors.initials: I
authors.lastname: Robinson
authors.forename: Irene
authors.initials: I
authors.lastname: Guerrini
authors.forename: Andrew
authors.initials: A
authors.lastname: McQuillin
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ungless
authors.forename: Hugh M D
authors.initials: HM
authors.lastname: Gurling
authors.forename: Marsha Y
authors.initials: MY
authors.lastname: Morgan
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.forename: David N
authors.initials: DN
authors.lastname: Stephens
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.forename: Howard C
authors.initials: HC
authors.lastname: Thomas
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D019973:Alcohol-Related Disorders / Q000235:genetics; D000818:Animals; D005260:Female; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009714:Nucleus Accumbens / Q000502:physiology; D017354:Point Mutation; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism
chemical_list: C546266:Gabrb1 protein, mouse; D011963:Receptors, GABA-A