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The novel imidazothienodiazepine inverse agonist RO19-4603 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 RO19-4603 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 GABAA-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 α4 containing GABAA diazepam insensitive (DI) receptors in the NA, may mediate in part, the RO19-4603 suppression of EtOH responding in EtOH-seeking P rats.

The present study investigated dose dependence and time course effects of the benzodiazepine (BDZ) partial inverse agonist, RO19-4603 (0.005–0.30 mg/kg) alone, and in combination with the BDZ receptor antagonists flumazenil, ZK 93426, and CGS 8216 (20 mg/kg) in selectively bred alcohol-preferring (P) rats provided a two-bottle choice test between ethanol (EtOH) (10% v/v), and a palatable saccharin (0.0125% g/v) solution. A single dose of R019-4603 as low as 0.009 mg/kg selectively reduced EtOH drinking during the initial 15 min of a 4 h access to 19−0% of control levels on day 1. The 0.08, 0.15 and 0.30 mg/kg doses of R019-4603 significantly reduced total EtOH intake in the 4 h access period to 57−45% of controls on day 1. On day 2, no R019-4603 injections were given; however, six of the seven doses of R019-4603 (0.009, 0.02, 0.04, 0.08, 0.15, and 0.30 mg/kg) continued to reduce EtOH intake to 42−3% of control levels at the initial 15 min interval, while the 0.005, 0.009, 0.08, and 0.30 mg/kg doses reduced total 4 h EtOH intake to 60-42% of controls. Saccharin intake was either not altered by R019-4603 or showed increases during the initial 15 min intervals and the total 4 h sessions on days 1 and 2. Food intake was also unaffected by R019-4603. The CGS 8216, but neither flumazenil nor ZK 93426, reliably reversed the RO19-4603-induced suppression of EtOH intake on days 1 and 2. That certain BDZ inverse agonists can attenuate motivated behavior for EtOH reinforcement over a prolonged time course may provide a possible therapeutic approach to reducing EtOH consumption associated with alcoholism.

The role of the dorsal striatum in mediating the sedation produced by a moderate (0.75 g/kg) and an intoxicating (1.25 g/kg) EtOH dose was investigated in the open field by determining the capacity of direct intrastriatal injections of RY 008, a partial inverse agonist of the benzodiazepine (BDZ) receptor, to antagonize EtOH's effects. SR 95531, the competitive high-affinity GABA A antagonist was used as a reference compound. Intrastriatal RY 008 (50, 500 ng) and SR 95531 (50 ng) antagonized the sedation produced by the 0.75 g/kg EtOH dose. However, RY 008 did not alter the sedation produced by the 1.25 g/kg dose. RY 008 alone was without effect. RY 008 also failed to negatively modulate GABAergic function at α 1 β 2 γ 2 or α 6 β 2 γ 2 receptor subtypes expressed in Xenopus oocytes . Intrastriatal modulation of the moderate EtOH dose was site specific: no antagonism by RY 008 after intraaccumbens infusions was observed. The results suggest that central GABA A -BDZ receptors in the dorsal striatum play an important role in mediating the sedation produced by a moderate EtOH dose in the open field.