title: Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice.
abstract: Alcohol use disorders are associated with single-nucleotide polymorphisms in GABRA2, the gene encoding the GABAAreceptor 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 GABAAreceptor sensitivity to endogenous ligands is involved in excessive alcohol drinking.
  
  
  
  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 GABAAreceptors 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.).
  
  
  
  Mice with BZD-insensitive α2-containing GABAAreceptors (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.
  
  
  
  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 GABAAreceptors by ALLO and THDOC; we postulate that neurosteroid action on α2-containing receptor may be necessary for escalated chronic EtOH intake.
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts. emily.newman@tufts.edu, ELnewman@gmail.com.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Newman
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Georgia
authors.initials: G
authors.lastname: Gunner
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Polly
authors.initials: P
authors.lastname: Huynh
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Darrel
authors.initials: D
authors.lastname: Gachette
authors.affiliation: Department of Neuroscience, Tufts University, Boston, Massachusetts.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, Massachusetts.|Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: DeBold
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.|Department of Neuroscience, Tufts University, Boston, Massachusetts.
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Miczek
mesh_terms: D064829:Alcohol Abstinence / Q000523:psychology; D000818:Animals; D063425:Binge Drinking / Q000235:genetics*; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D017354:Point Mutation; D011803:Quinine; D011897:Random Allocation; D011963:Receptors, GABA-A / Q000235:genetics*; D012919:Social Behavior; D013395:Sucrose
chemical_list: C493920:Gabra2 protein, mouse; D011963:Receptors, GABA-A; D013395:Sucrose; D011803:Quinine
keywords: Alcohol Use Disorder; Binge-Like Drinking; Chronic Alcohol Drinking; Forced Alcohol Abstinence; Gabra2