title: Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice.
abstract: GABA(A) receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABA(A) receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABA(A) receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABA(A) receptors are necessary for BZs to exert their effects on conditioned fear responses. Our findings illustrate both an overlap and a divergence between the GABA(A) receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABA(A) receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABA(A) receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored.
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
authors.forename: Kiersten S
authors.initials: KS
authors.lastname: Smith
authors.forename: Elif
authors.initials: E
authors.lastname: Engin
authors.forename: Edward G
authors.initials: EG
authors.lastname: Meloni
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002707:Chlordiazepoxide / Q000494:pharmacology / Q000627:therapeutic use*; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use*; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology
chemical_list: D014151:Anti-Anxiety Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D002707:Chlordiazepoxide; D003975:Diazepam