The novel benzodiazepine inverse agonist RO19-4603 antagonizes ethanol motivated behaviors: neuropharmacological studies

The novel imidazothienodiazepine inverse agonist R019-4603 has been reported to attenuate EtOH intake in home cage drinking tests for at least 24 h post-drug administration after systemic administration. In the present study, selectively bred alcohol-preferring (P) rats were trained under a concurrent (FR4-FR4) operant schedule to press one lever for EtOH (10% v/v) and another lever for saccharin (0.05% or 0.75% g/v), then dose-response and timecourse effects of R019-4603 were evaluated, Systemic RO19-4603 injections (0.0045-0.3 mg/kg; i.p.) profoundly reduced EtOH responding by as much as 97% of vehicle control on day 1. No effects were seen on saccharin responding except with the highest dose level (0.3 mg/kg). In a second experiment, microinjections of RO19-4603 (2-100 ng) directly into the nucleus accumbens (NA) suppressed EtOH responding on day 1 by as much as 53% of control: Control injections dorsal to the NA or ventral tegmental area did not significantly alter EtOH or saccharin responding, On day 2, rats in both experiments received no RO19-4603 treatments; however, all 7 of the i.p. doses, and all 3 of the intra-NA infusions continued to significantly suppress EtOH responding by 43-85% of vehicle control levels. In addition, i.p. injections of RO19-4603 produced a dose-dependent decrease in the slope of the cumulative record for EtOH responding, while concomitantly producing a dose-dependent increase in the slope for saccharin responding. RO19-4603's actions appear to be mediated via recognition sites at GABA(A)-BDZ receptors which regulate EtOH reinforcement, and not via mechanisms regulating ingestive behaviors. Based on recent in situ hybridization studies in our laboratory, we hypothesize that occupation of alpha(4) containing GABA(A) diazepam insensitive (DI) receptors in the NA, may mediate in part, the R019-4603 suppression of EtOH responding in EtOH-seeking P rats. (C) 1998 Elsevier Science B.V.