title: A Pharmacogenetic 'Restriction-of-Function' Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by α5-Containing GABAA Receptors in Mice.
abstract: Benzodiazepines have been widely used for their anxiolytic actions. However, the contribution of GABAA receptor subtypes to anxiolysis is still controversial. Studies with mutant mice harboring diazepam-insensitive α-subunits α1, α2, α3, or α5 have revealed that α2-containing GABAA receptors (α2-GABAARs) are required for diazepam-induced anxiolysis, with no evidence for an involvement of any other α-subunit, whereas TP003, described as a selective modulator of α3-containing GABAA receptors, was shown to be anxiolytic. Here, we describe a novel, systematic approach to evaluate the role of positive allosteric modulation of each of the four diazepam-sensitive α-subtypes in anxiety-related behavioral paradigms. By combining H to R point mutations in three out of the four diazepam-sensitive α-subunits in mice with a 129X1/SvJ background, diazepam becomes a subtype-specific modulator of the remaining non-mutated α-subtype. Modulation of α5-GABAARs, but not of α2-GABAARs, increased the time in the light side of the light-dark box as well as open-arm exploration in the elevated plus maze. In contrast, modulation of α3-GABAARs decreased open-arm exploration, whereas modulation of α2-GABAARs increased time in the center in the open-field test. Modulation of any single α-subtype had no effect on stress-induced hyperthermia. Our results provide evidence that modulation of α5-GABAARs elicits anxiolytic-like actions, whereas our data do not provide evidence for an anxiolytic-like action of α3-GABAARs. Thus, α5-GABAARs may be suitable targets for novel anxiolytic drugs.
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Behlke
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Foster
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Benke
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Benham
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Nathanson
authors.affiliation: Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, Hong Kong.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.|Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zürich, Switzerland.
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Elif
authors.initials: E
authors.lastname: Engin
authors.affiliation: Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000235:genetics*; D001345:Autoradiography; D003623:Dark Adaptation / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005334:Fever / Q000188:drug therapy / Q000209:etiology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010597:Pharmacogenetics; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013315:Stress, Psychological / Q000150:complications
chemical_list: C552286:4,2'-difluoro-5'-(8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo(1,2-a)pyridin-3-yl)biphenyl-2-carbonitrile; D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D007093:Imidazoles; D011725:Pyridines; D011963:Receptors, GABA-A