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

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 (Ki approximately 0.98 microM). 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-6-4H-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.

The opioid receptor antagonist nalmefene reduces responding maintained by ethanol presentation: preclinical studies in ethanol-preferring and outbred Wistar rats.

Nalmefene, the 6-methylene derivative of naltrexone, was examined after subcutaneous (s.c.) (0.0001 to 8.0 mg/kg) and oral (10 to 80.0 mg/kg) administration in ethanol (EtOH)-preferring rats whose responding (i.e., lever pressing) was maintained by the presentation of EtOH. Naltrexone (0.01 to 40 mg/kg) was used as a reference opioid antagonist. EtOH (10% v/v) and saccharin (0.025 to 0.1% w/v) solutions were concurrently available for 1 hr each day under a two-lever, fixed-ratio schedule in which four responses on one lever produced the EtOH solution and four responses on the other lever produced the saccharin solution. When basal response rates for saccharin were 10% that of EtOH, all routes of nalmefene administration reduced control levels of responding maintained by EtOH by 38 to 84%. When basal response rates for saccharin-maintained responding were 60% or 82% that of EtOH, only lower s.c. naltrexone (e.g., 0.01 to 0.025 mg/kg) and nalmefene (e.g., 0.01 to 0.10 mg/kg) doses produced a selective dose-dependent suppression of EtOH-maintained responding. Higher nalmefene (0.25 to 8.0 mg/kg) and naltrexone (1.0 to 20.0 mg/kg) doses failed to produce a dose-dependent suppression on EtOH or saccharin maintained responding. Both antagonists suppressed responding maintained by EtOH primarily during the initial 10-min period, with little additional suppression occurring across the remainder of the 60-min period. Subcutaneous nalmefene was 3200- to 6400-fold more potent than oral nalmefene, suggesting bioavailability was optimized using the s.c. route. Nalmefene (0.5 mg/kg, s.c.) treatment for 10 consecutive days produced mild tolerance development, whose effects dissipated by day 8. Naltrexone (10 to 40 mg/kg) and nalmefene (1.5 to 3.0 mg/kg), given 8 to 24 hr before the test session, reduced control levels of responding maintained by EtOH by 82%. Thus, immediate opioid receptor occupancy was not required to observe antagonism. These data demonstrate that, under a variety of experimental conditions, nalmefene is an effective antagonist of responding maintained by EtOH and lend support to clinical reports that nalmefene may function as an alternative pharmacotherapy to naltrexone to reduce EtOH-motivated behavior and prevent relapse.