title: Mice lacking Gad2 show altered behavioral effects of ethanol, flurazepam and gabaxadol.
abstract: Gamma-aminobutyric acid (GABA) is synthesized in brain by two isoforms of glutamic acid decarboxylase (Gad), Gad1 and Gad2. Gad1 provides most of the GABA in brain, but Gad2 can be rapidly activated in times of high GABA demand. Mice lacking Gad2 are viable whereas deletion of Gad1 is lethal. We produced null mutant mice for Gad2 on three different genetic backgrounds: predominantly C57BL/6J and one or two generations of backcrossing to 129S1/SvimJ (129N1, 129N2). We used these mice to determine if actions of alcohol are regulated by synthesis of GABA from this isoform. We also studied behavioral responses to a benzodiazepine (flurazepam) and a GABAA receptor agonist (gabaxadol). Deletion of Gad2 increased ethanol palatability and intake and slightly reduced the severity of ethanol-induced withdrawal, but these effects depended strongly on genetic background. Mutant mice on the 129N2 background showed the above three ethanol behavioral phenotypes, but the C57BL/6J inbred background did not show any of these phenotypes. Effects on ethanol consumption also depended on the test as the mutation did not alter consumption in limited access models. Deletion of Gad2 reduced the effect of flurazepam on motor incoordination and increased the effect of extrasynaptic GABAA receptor agonist gabaxadol without changing the duration of loss of righting reflex produced by these drugs. These results are consistent with earlier proposals that deletion of Gad2 (on 129N2 background) reduces synaptic GABA but also suggest changes in extrasynaptic receptor function.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas, 1 University Station, Austin, TX 78712-0159, USA. yablednov@mail.utexas.edu
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Blednov
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Walker
authors.forename: Sangeetha V
authors.initials: SV
authors.lastname: Iyer
authors.forename: Gregg
authors.initials: G
authors.lastname: Homanics
authors.forename: Adron R
authors.initials: AR
authors.lastname: Harris
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000430:Alcohol Withdrawal Delirium / Q000235:genetics; D000818:Animals; D001569:Benzodiazepines / Q000633:toxicity*; D001921:Brain / Q000187:drug effects; D003433:Crosses, Genetic; D000431:Ethanol / Q000097:blood / Q000633:toxicity*; D005479:Flurazepam / Q000633:toxicity*; D018755:GABA Agonists / Q000633:toxicity*; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics*; D007555:Isoxazoles / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009048:Motor Skills / Q000187:drug effects*; D010641:Phenotype; D004856:Postural Balance / Q000187:drug effects* / Q000235:genetics*; D013045:Species Specificity; D013649:Taste / Q000187:drug effects / Q000235:genetics
chemical_list: D018755:GABA Agonists; D007555:Isoxazoles; D001569:Benzodiazepines; D000431:Ethanol; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D005479:Flurazepam; C015542:gaboxadol