GABRA2 POINT-MUTATION: INCREASED BINGE-LIKE AND BLUNTED DEPENDENCE-INDUCING ALCOHOL DRINKING BY MICE
Abstract: Alcohol use disorders have been associated with SNPs in GABRA2, the gene encoding the GABAA receptor α2-subunit in humans. Deficient GABAergic functioning is linked to impulse control disorders including intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear if α2-containing GABAA receptor sensitivity to endogenous ligands is involved in excessive alcohol ... read moredrinking. We assessed mice harboring specific amino acid point-substitutions in the α2-subunit protein sequence. Mutants rendered insensitive to GABAergic modulation by benzodiazepines (H101R), allopregnanolone or THDOC (Q241M), or to high concentrations of ethanol (S270H/L277A) at α2-containing GABAA receptors were assessed for binge-like, moderate or dependence-inducing drinking. Mice with benzodiazepine-insensitive α2-containing GABAA receptors escalated their binge-like drinking, achieving blood ethanol concentrations of 127±19 mg/dl in 4h. Clinical findings report reduced BZD-binding sites in the cortex of dependent patients; the present findings suggest a specific role for BZD-sensitive α2-containing receptors. Mice harboring the Q241M mutation showed blunted moderate and dependence-inducing intake. This amino acid is necessary for neurosteroid positive modulation and activation of GABAA receptors; we postulate that neurosteroid action on α2-containing receptor may be necessary for escalated chronic ethanol intake. Like wild-type controls, S270H/L277A mutant mice consumed excessive amounts of alcohol but, unlike controls, they did not show withdrawal-induced deficits in social behavior. These findings suggest a role of amino acid residues: 1.) H101 for species-typical binge-like drinking, 2.) Q241 for escalated chronic, dependence-inducing drinking, and 3.) S270 and/or L277 for the development of alcohol withdrawal-associated social deficits which may increase the chance of relapse to drug taking.
Thesis (M.S.)--Tufts University, 2016.
Submitted to the Dept. of Psychology.
Advisor: Klaus Miczek.
Committee: Joseph DeBold, and Uwe Rudolph.
Keywords: Psychology, Neurosciences, and Behavioral psychology.read less