BENZODIAZEPINE RECEPTOR LIGANDS WITH DIFFERENT INTRINSIC EFFICACIES ALTER ETHANOL INTAKE IN ALCOHOL-NONPREFERRING (NP) RATS

Benzodiazepine (BDZ) receptor ligands with varying intrinsic efficacie s [R019-4603, 0.02-0.15 mg/kg; FG 7142 1-16 mg/kg; DMCM, 1-8 mg/kg;RO1 6-6028 (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 2 2-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 int ake 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, R019-46 03, the imidazothienodiazepine partial inverse agonist reduced EtOH in take 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 suppresse d drinking of the EtOH solution at the 60-minute interval, and the 0.1 5-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, t he full beta-carboline inverse agonist, significantly reduced wafer in take at 15 minutes (4 and 8 mg/kg), and the same doses caused a substa ntial increase in EtOH drinking at the 120-minute interval. The anxiol ytic agent bretazenil (16 and 32 mg/kg) increased EtOH consumption dur ing the initial 15 minutes to 270% to 425% of control levels, and wate r 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 findi ngs support existing evidence suggesting that BDZ receptor ligands may modify neuronal processes that mediate some reinforcing and/or aversi ve properties of alcohol. They further demonstrate a potential importa nce of the GABA(A)-BDZ receptor complex in mediating palatability- (en vironmentally) induced EtOH drinking even in rats selectively bred for low alcohol preference.