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Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge‐Like and Blunted Chronic Drinking by Mice
Author(s) -
Newman Emily L.,
Gunner Georgia,
Huynh Polly,
Gachette Darrel,
Moss Stephen J.,
Smart Trevor G.,
Rudolph Uwe,
DeBold Joseph F.,
Miczek Klaus A.
Publication year - 2016
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13215
Subject(s) - allopregnanolone , gabaa receptor , pregnanolone , binge drinking , medicine , endocrinology , abstinence , alcohol use disorder , alcohol , neuroactive steroid , pharmacology , psychology , chemistry , receptor , psychiatry , biochemistry , alcohol consumption
Background Alcohol use disorders are associated with single‐nucleotide polymorphisms in GABRA 2 , the gene encoding the GABA A receptor α 2‐subunit in humans. Deficient GABA ergic functioning is linked to impulse control disorders, intermittent explosive disorder, and to drug abuse and dependence, yet it remains unclear whether α 2‐containing GABA A receptor sensitivity to endogenous ligands is involved in excessive alcohol drinking. Methods Male wild‐type (Wt) C57 BL /6J and point‐mutated mice rendered insensitive to GABA ergic modulation by benzodiazepines (BZD; H101R), allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC; Q241M), or high concentrations of ethanol (EtOH) (S270H/L277A) at α 2‐containing GABA A 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 Et OH ‐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 GABA A 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 GABA A receptors by ALLO and THDOC ; we postulate that neurosteroid action on α 2‐containing receptor may be necessary for escalated chronic EtOH intake.