title: Selective GABAA alpha5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol.
abstract: BACKGROUND
  Previous research has implicated the alpha5-containing GABAA receptors of the hippocampus in the reinforcing properties of alcohol. In the present study, a selective GABAA alpha5 benzodiazepine inverse agonist (e.g., RY 023) was used in a series of in vivo and in vitro studies to determine the significance of the alpha5-receptor in the neurobehavioral actions of alcohol.
  
  
  METHODS
  In experiment one, systemic injections of RY 023 (1 to 10 mg/kg IP) dose-dependently reduced ethanol-maintained responding by 52% to 86% of controls, whereas bilateral hippocampal infusions (0.3 to 20 microg) reduced responding by 66% to 84% of controls. Saccharin responding was reduced only with the highest intraperitoneal (e.g., 10 mg) and microinjected (e.g., 20 microg) doses. In experiment two, RY 023 (3.0 to 15 mg/kg IP) reversed the motor-impairing effects of a moderate dose of alcohol (0.75 g/kg) on an oscillating bar task in the absence of intrinsic effects. In the open field, RY 023 (3.0 to 7.5 mg/kg) produced intrinsic effects alone but attenuated the suppression of the 1.25 g/kg ethanol dose. Because the diazepam-insensitive receptors (e.g., alpha4 and alpha6) have been suggested to play a role in alcohol motor impairing and sedative actions, experiment three compared the efficacy of RY 023 with Ro 15-4513 and two prototypical benzodiazepine antagonists (e.g., flumazenil and ZK 93426) across the alpha4beta3gamma2-, alpha5beta3gamma2-, and alpha6beta3gamma2-receptor subtypes in Xenopus oocytes.
  
  
  RESULTS
  RY 023 produced classic inverse agonism at all receptor subtypes, whereas Ro15-4513 and the two antagonists displayed a neutral or agonistic profile at the diazepam-insensitive receptors.
  
  
  CONCLUSIONS
  Overall, the results extend our previous findings by demonstrating that an alpha5-subtype ligand is capable of attenuating not only the rewarding action of alcohol but also its motor impairing and sedative effects. We propose that these actions are mediated in part by the alpha5-receptors of the hippocampus. The hippocampal alpha5-receptors could represent novel targets in understanding the neuromechanisms regulating the neurobehavioral actions of alcohol in humans.
authors.affiliation: Psychobiology Program, Department of Psychology, Indiana University-Purdue University, Indianapolis, Indiana 46202-3275, USA.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Cook
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Foster
authors.forename: William J A
authors.initials: WJ
authors.lastname: Eiler
authors.forename: Peter F
authors.initials: PF
authors.lastname: McKay
authors.forename: James
authors.initials: J
authors.lastname: Woods
authors.forename: Scott C
authors.initials: SC
authors.lastname: Harvey
authors.forename: Marin
authors.initials: M
authors.lastname: Garcia
authors.forename: Collette
authors.initials: C
authors.lastname: Grey
authors.forename: Shannan
authors.initials: S
authors.lastname: McCane
authors.forename: Dynesha
authors.initials: D
authors.lastname: Mason
authors.forename: Rancia
authors.initials: R
authors.lastname: Cummings
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001569:Benzodiazepines / Q000819:agonists*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D018756:GABA Antagonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000427:Alcohol Deterrents; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; C506802:RY 023; D001569:Benzodiazepines; D000431:Ethanol