The effects of the novel benzodiazepine receptor inverse agonist Ru 34000 on ethanol-maintained behaviors

Abstract Ru 34000 [5-ethyl-7-methoxy-imidazo (1,2-a) pyrimidin-2-yl cyclopropyl methanone] is a novel imidazopyrimidine benzodiazepine inverse agonist that exhibits low affinity for central benzodiazepine receptors ( K i ≈0.98 μ M). The present study examined the in vivo actions of Ru 34000 (0.5–5 mg/kg) following intraperitoneal (i.p.), subcutaneous (s.c), oral (p.o.), and intraventral tegmental administration in alcohol-preferring (P) rats trained under a concurrent operant schedule (FR4–FR4) for ethanol (10% v/v) and a palatable saccharin (0.025% or 0.75% w/v) reinforcer. Ru 34000 (i.p., s.c., p.o.) markedly reduced ethanol responding by 28–96% of control levels without affecting saccharin responding, except for the highest dose level. Clear dose-dependent suppressant effects were observed with all routes of administration on ethanol responding. Flumazenil [ethyl-8-fluro-5, 6-dihydro-5-methyl-6-4 H -imidazo [1,5-a]-[1,4]-benzodiazepine-3-carboxylate] (6 mg/kg; i.p.), a benzodiazepine receptor antagonist reversed the Ru 34000-reduction of ethanol responding, suggesting that the effects were mediated at the benzodiazepine receptor. Bilateral microinjections of Ru 34000 (50, 100, 200 ng) into the ventral tegmental area dose-dependently reduced ethanol responding by as much as 97% of control levels. The results suggest that the in vivo actions of Ru 34000 are determined not only by its binding affinity, but also by its bioavailability at active benzodiazepine sites and route of drug administration. Low affinity imidazopyrimidines may be useful pharmacological probes to further understand the role of the GABA A -benzodiazepine receptor complex in ethanol motivated behaviors.