title: Benzodiazepine receptor ligands with different intrinsic efficacies alter ethanol intake in alcohol-nonpreferring (NP) rats.
abstract: Benzodiazepine (BDZ) receptor ligands with varying intrinsic efficacies [RO19-4603, 0.02-0.15 mg/kg; FG 7142 1-16 mg/kg; DMCM, 1-8 mg/kg; RO16-6028 (bretazenil), 8-32 mg/kg] in modulating GABAergic activity were examined for the ability to alter palatability-induced ethanol (EtOH) intake in the alcohol-nonpreferring (NP) line of rats. NP rats on a 22-hour fluid-deprivation schedule were given 2-hour daily access to a 10% (v/v) EtOH/3% (g/v) polycose solution and water. Average EtOH intake was 2.1 +/- 0.2 g/kg/2 hours, and water intake was 17.1 +/- 0.9 ml/2 hours. During the initial 15 minutes of the 2-hour session, RO19-4603, the imidazothienodiazepine partial inverse agonist reduced EtOH intake to 19% of control values at 0.04 mg/kg and completely suppressed drinking of the EtOH solution at 0.15 mg/kg. Twenty-four-hour postdrug administration, the 0.08-mg/kg dose of RO19-4603 completely suppressed drinking of the EtOH solution at the 60-minute interval, and the 0.15-mg/kg dose reduced intake to 20% of control levels at the 15-minute interval. FG 7142, the partial beta-carboline inverse agonist reduced EtOH drinking at the 60-minute interval with the 1-mg/kg dose, and the 16-mg/kg dose reduced water intake at the 15-minute interval. DMCM, the full beta-carboline inverse agonist, significantly reduced water intake at 15 minutes (4 and 8 mg/kg), and the same doses caused a substantial increase in EtOH drinking at the 120-minute interval. The anxiolytic agent bretazenil (16 and 32 mg/kg) increased EtOH consumption during the initial 15 minutes to 270% to 425% of control levels, and water intake increased by the end of the 2-hour session to as much as 210% of control following administration of the 32-mg/kg dose. These findings support existing evidence suggesting that BDZ receptor ligands may modify neuronal processes that mediate some reinforcing and/or aversive properties of alcohol. They further demonstrate a potential importance of the GABAA-BDZ receptor complex in mediating palatability- (environmentally) induced EtOH drinking even in rats selectively bred for low alcohol preference.
authors.affiliation: Department of Psychology, Indianapolis, IN 46202-3275, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: June
authors.forename: J M
authors.initials: JM
authors.lastname: Murphy
authors.forename: R L
authors.initials: RL
authors.lastname: Hewitt
authors.forename: T L
authors.initials: TL
authors.lastname: Greene
authors.forename: M
authors.initials: M
authors.lastname: Lin
authors.forename: J J
authors.initials: JJ
authors.lastname: Mellor-Burke
authors.forename: L
authors.initials: L
authors.lastname: Lumeng
authors.forename: T K
authors.initials: TK
authors.lastname: Li
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005936:Glucans / Q000494:pharmacology; D008297:Male; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013997:Time Factors
chemical_list: D001381:Azepines; D005936:Glucans; D011963:Receptors, GABA-A; D000431:Ethanol; C056530:Ro 19-4603