title: Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines.
abstract: The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.
authors.affiliation: The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom. rebecca_dias@merck.com
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dias
authors.forename: Wayne F A
authors.initials: WF
authors.lastname: Sheppard
authors.forename: Rosa L
authors.initials: RL
authors.lastname: Fradley
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Garrett
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Stanley
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Tye
authors.forename: Simon
authors.initials: S
authors.lastname: Goodacre
authors.forename: Rachael J
authors.initials: RJ
authors.lastname: Lincoln
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Rachel
authors.initials: R
authors.lastname: Conley
authors.forename: David
authors.initials: D
authors.lastname: Hallett
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Humphries
authors.forename: Sally A
authors.initials: SA
authors.lastname: Thompson
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wafford
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.forename: J Luis
authors.initials: JL
authors.lastname: Castro
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Whiting
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rosahl
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: David S
authors.initials: DS
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding / Q000502:physiology; D021122:Protein Subunits / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D012453:Saimiri
chemical_list: D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; C546257:GABRA3 protein, human; C546258:Gabra3 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A; D001569:Benzodiazepines