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Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice

Newman, EL; Gunner, G; Huynh, P; Gachette, D; Moss, SJ; Smart, TG; Rudolph, U; ... Miczek, KA; + view all (2016) Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice. Alcoholism: Clinical and Experimental Research , 40 (11) pp. 2445-2455. 10.1111/acer.13215. Green open access

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Abstract

BACKGROUND: Alcohol use disorders are associated with single-nucleotide polymorphisms in GABRA2, the gene encoding the GABAA receptor α2-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 α2-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 α2-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 α2-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 α2-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 α2-containing receptor may be necessary for escalated chronic EtOH intake.

Type: Article
Title: Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/acer.13215
Publisher version: http://dx.doi.org/10.1111/acer.13215
Language: English
Additional information: This is the peer reviewed version of the following article: Newman, E. L., Gunner, G., Huynh, P., Gachette, D., Moss, S. J., Smart, T. G., Rudolph, U., DeBold, J. F. and Miczek, K. A. (2016), Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice. Alcohol Clin Exp Res, 40: 2445–2455., which has been published in final form at http://dx.doi.org/10.1111/acer.13215. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Keywords: Science & Technology, Life Sciences & Biomedicine, Substance Abuse, Gabra2, Alcohol Use Disorder, Binge-Like Drinking, Forced Alcohol Abstinence, Chronic Alcohol Drinking, Gamma-Aminobutyric-Acid, Alpha-2-Containing Gaba(A) Receptors, A Receptors, Benzodiazepine-Receptor, Ethanol Drinking, C57Bl/6J Mice, Knockin Mice, Dependence, Subunit, Association
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1544306
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