THE NOVEL BENZODIAZEPINE INVERSE AGONIST RO19-4603 ANTAGONIZES ETHANOL MOTIVATED BEHAVIORS - NEUROPHARMACOLOGICAL STUDIES

The novel imidazothienodiazepine inverse agonist R019-4603 has been re ported to attenuate EtOH intake in home cage drinking tests for at lea st 24 h post-drug administration after systemic administration. In the present study, selectively bred alcohol-preferring (P) rats were trai ned under a concurrent (FR4-FR4) operant schedule to press one lever f or 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 evaluate d, Systemic RO19-4603 injections (0.0045-0.3 mg/kg; i.p.) profoundly r educed EtOH responding by as much as 97% of vehicle control on day 1. No effects were seen on saccharin responding except with the highest d ose level (0.3 mg/kg). In a second experiment, microinjections of RO19 -4603 (2-100 ng) directly into the nucleus accumbens (NA) suppressed E tOH responding on day 1 by as much as 53% of control: Control injectio ns dorsal to the NA or ventral tegmental area did not significantly al ter EtOH or saccharin responding, On day 2, rats in both experiments r eceived no RO19-4603 treatments; however, all 7 of the i.p. doses, and all 3 of the intra-NA infusions continued to significantly suppress E tOH responding by 43-85% of vehicle control levels. In addition, i.p. injections of RO19-4603 produced a dose-dependent decrease in the slop e of the cumulative record for EtOH responding, while concomitantly pr oducing a dose-dependent increase in the slope for saccharin respondin g. RO19-4603's actions appear to be mediated via recognition sites at GABA(A)-BDZ receptors which regulate EtOH reinforcement, and not via m echanisms regulating ingestive behaviors. Based on recent in situ hybr idization studies in our laboratory, we hypothesize that occupation of alpha(4) containing GABA(A) diazepam insensitive (DI) receptors in th e NA, may mediate in part, the R019-4603 suppression of EtOH respondin g in EtOH-seeking P rats. (C) 1998 Elsevier Science B.V.