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 g-aminobutyric acidA receptor (GABAAR) b1 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.

• Autores: Martínez, Alonso; Anstee, Quentin M.; Knapp, Susanne; Maguire, Edward P.; Hosie, Alastair M.; Thomas, Philip; Mortensen, Martin; Bhome, Rohan; Walker, Sophie E.; Dixon, Claire I.; Ruparelia, Kush; Montagnese, Sara; Kuo, Yu-Ting; Herlihy, Amy; Bell, Jimmy D.; Robinson, Iain; Guerrini, Irene; McQuillin, Andrew; Fisher, Elizabeth M.C.; Ungless, Mark A.; Gurling, Hugh M.D.; Morgan, Marsha Y.; Brown, Steve D.M.; Stephens, David N.; Belelli, Delia; Lambert, Jeremy J.; Smart, Trevor G.; Thomas, Howard C.
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2024
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/43358
• Acceso en línea: https://hdl.handle.net/10495/43358
• Palabra clave: Consumo de Bebidas Alcohólicas; Alcohol Drinking; Trastornos Relacionados con Alcohol; Alcohol-Related Disorders; Genes Dominantes; Genes, Dominant; Células HEK293; HEK293 Cells; Ratones Endogámicos BALB C; Mice, Inbred BALB C; Ratones Endogámicos C3H; Mice, Inbred C3H; Núcleo Accumbens; Nucleus Accumbens; Mutación Puntual; Point Mutation; Receptores de GABA-A; Receptors, GABA-A; https://id.nlm.nih.gov/mesh/D000428; https://id.nlm.nih.gov/mesh/D019973; https://id.nlm.nih.gov/mesh/D005799; https://id.nlm.nih.gov/mesh/D057809; https://id.nlm.nih.gov/mesh/D008807; https://id.nlm.nih.gov/mesh/D008809; https://id.nlm.nih.gov/mesh/D009714; https://id.nlm.nih.gov/mesh/D017354; https://id.nlm.nih.gov/mesh/D011963
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/2.5/co/