title: Anxiogenic properties of an inverse agonist selective for alpha3 subunit-containing GABA A receptors.
abstract: Alpha3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABA(A) receptors containing an alpha3 rather than an alpha1, alpha2 or alpha5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of alpha3IA are most probably mediated by the alpha3 subtype. Alpha3IA has good CNS penetration in rats and mice as measured using a [(3)H]Ro 15-1788 in vivo binding assay. At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. alpha1-containing receptors), alpha3IA (30 mg kg(-1) i.p.), like the nonselective partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain-pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic-like effect that could be blocked with the benzodiazepine antagonist Ro 15-1788 (flumazenil). Neurochemically, alpha3IA (30 mg kg(-1) i.p.) as well as FG 7142 (15 mg kg(-1) i.p.) increased the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle-treated animals, a response that mimicked that seen following immobilisation stress. Taken together, these data demonstrate that an inverse agonist selective for GABA(A) receptors containing an alpha3 subunit is anxiogenic, and suggest that since alpha3-containing GABA(A) receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. John_Atack@Merck.com
authors.forename: John R
authors.initials: JR
authors.lastname: Atack
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hutson
authors.forename: Neil
authors.initials: N
authors.lastname: Collinson
authors.forename: George
authors.initials: G
authors.lastname: Marshall
authors.forename: Graham
authors.initials: G
authors.lastname: Bentley
authors.forename: Christopher
authors.initials: C
authors.lastname: Moyes
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cook
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: Keith
authors.initials: K
authors.lastname: Wafford
authors.forename: Ruth M
authors.initials: RM
authors.lastname: McKernan
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000523:psychology; D001923:Brain Chemistry / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018755:GABA Agonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D011994:Recombinant Proteins; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D002243:Carbolines; D018755:GABA Agonists; C546257:GABRA3 protein, human; C546258:Gabra3 protein, mouse; C546259:Gabra3 protein, rat; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; C035874:FG 7142