title: Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.
abstract: Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.
authors.affiliation: Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. Ruth_McKernan@Merck.com
authors.forename: R M
authors.initials: RM
authors.lastname: McKernan
authors.forename: T W
authors.initials: TW
authors.lastname: Rosahl
authors.forename: D S
authors.initials: DS
authors.lastname: Reynolds
authors.forename: C
authors.initials: C
authors.lastname: Sur
authors.forename: K A
authors.initials: KA
authors.lastname: Wafford
authors.forename: J R
authors.initials: JR
authors.lastname: Atack
authors.forename: S
authors.initials: S
authors.lastname: Farrar
authors.forename: J
authors.initials: J
authors.lastname: Myers
authors.forename: G
authors.initials: G
authors.lastname: Cook
authors.forename: P
authors.initials: P
authors.lastname: Ferris
authors.forename: L
authors.initials: L
authors.lastname: Garrett
authors.forename: L
authors.initials: L
authors.lastname: Bristow
authors.forename: G
authors.initials: G
authors.lastname: Marshall
authors.forename: A
authors.initials: A
authors.lastname: Macaulay
authors.forename: N
authors.initials: N
authors.lastname: Brown
authors.forename: O
authors.initials: O
authors.lastname: Howell
authors.forename: K W
authors.initials: KW
authors.lastname: Moore
authors.forename: R W
authors.initials: RW
authors.lastname: Carling
authors.forename: L J
authors.initials: LJ
authors.lastname: Street
authors.forename: J L
authors.initials: JL
authors.lastname: Castro
authors.forename: C I
authors.initials: CI
authors.lastname: Ragan
authors.forename: G R
authors.initials: GR
authors.lastname: Dawson
authors.forename: P J
authors.initials: PJ
authors.lastname: Whiting
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D001386:Azides / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000819:agonists / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000493:pharmacokinetics; D005464:Fluorobenzenes / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001386:Azides; D005464:Fluorobenzenes; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D008024:Ligands; D011963:Receptors, GABA-A; D014230:Triazoles; D001569:Benzodiazepines; D005442:Flumazenil; C409903:L 838,417; C042957:Ro 15-4513; D003975:Diazepam