Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge‐Like and Blunted Chronic Drinking by Mice. (26th September 2016)

• Record Type: Journal Article
• Authors: Newman, Emily L.; Gunner, Georgia; Huynh, Polly; Gachette, Darrel; Moss, Stephen J.; Smart, Trevor G.; Rudolph, Uwe; DeBold, Joseph F.; Miczek, Klaus A.
• Is Part Of: Alcoholism. Volume 40:Number 11(2016)
• Page Start: 2445
• Page End: 2455
• Publication Date: 2016-09-26
• Subjects: Gabra2 -- Alcohol Use Disorder -- Binge‐Like Drinking -- Forced Alcohol Abstinence -- Chronic Alcohol Drinking; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.13215
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract : Background: Alcohol use disorders are associated with single‐nucleotide polymorphisms in GABRA2, the gene encoding the GABAA receptor α 2‐subunit in humans. Deficient GABAergic functioning is linked to impulse control disorders, intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear whether α 2‐containing GABAA receptor sensitivity to endogenous ligands is involved in excessive alcohol drinking. Methods: Male wild‐type (Wt) C57BL/6J and point‐mutated mice rendered insensitive to GABAergic modulation by benzodiazepines (BZD; H101R), allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC; Q241M), or high concentrations of ethanol (EtOH) (S270H/L277A) at α 2‐containing GABAA receptors were assessed for their binge‐like, moderate, or escalated chronic drinking using drinking in the dark, continuous access (CA) and intermittent access (IA) to alcohol protocols, respectively. Social approach by mutant and Wt mice in forced alcohol abstinence was compared to approach by EtOH‐naïve controls. Social deficits in forced abstinence were treated with allopregnanolone (0, 3.0, 10.0 mg/kg, intraperitoneal [i.p.]) or midazolam (0, 0.56, 1.0 mg/kg, i.p.). Results: Mice with BZD‐insensitive α 2‐containing GABAA receptors (H101R) escalated their binge‐like drinking. Mutants harboring the Q241M point substitution in Gabra2 showed blunted chronic intake in the CA and IA protocols. S270H/L277A mutants consumed excessive amounts of alcohol but, unlike wild‐types, they did not show forced abstinence‐induced social deficits. Conclusions: These findings suggest a role for: (i) H101 in species‐typical binge‐like drinking, (ii) Q241 in escalated chronic drinking, and (iii) S270 and/or L277 in the development of forced abstinence‐associated social deficits. Clinical findings report reduced BZD‐binding sites in the cortex of dependent patients; the present findings suggest a specific role for BZD‐sensitive α 2‐containing receptors. In addition, amino acid residue 241 in Gabra2 is necessary for positive modulation and activation of GABAA receptors by ALLO and THDOC; we postulate that neurosteroid action on α 2‐containing receptor may be necessary for escalated chronic EtOH intake. Abstract : Alcohol dependence is associated with single‐nucleotide polymorphisms in GABRA2, the gene encoding the GABAA receptor α 2‐subunit. Gabra2 point‐mutated mice consumed alcohol in drinking‐in‐the‐dark, continuous, or intermittent access to alcohol protocols. Compared to wild‐types, α 2(H101R) mice with benzodiazepine‐insensitive α 2‐containing receptors (HR) escalated their binge‐like intake and α 2(Q241M) mutants with allopregnanolone‐ and THDOC‐insensitive α 2‐containing receptors reduced their chronic drinking (QM). These findings suggest distinctive roles for select amino acids in the Gabra2 mouse gene in binge‐like and chronic alcohol intake.