State-dependent effects of atypical benzodiazepine-receptor agonists

The state-dependent effect of the BZ-receptor agonist diazepam (1.25-10 mg/kg), the partial agonist FG 8205 (0.5-4.0 mg/kg) and the BZ1-receptor agonist zolpidem (0.25-2 mg/kg) were investigated in rats. During daily sessions, animals were trained to acquire FR10 lever pressing for food reinforcement whilst under the influence of the agonists, using an operant technique. Forty-eight hours after the final training session under drug, their performance of the FR10 was evaluated during a test session, carried out following vehicle administration only. Neither diazepam, nor FG 8205 impaired acquisition of the task. In the group treated with 2 mg/kg zolpidem, six out of eight rats failed to learn within 20 sessions, but the smaller doses were without effect on acquisition. When drug treatment was withdrawn, there was evidence that all three of the agonists tested produced state-dependency. This was apparent in the form of longer latencies to obtain reinforcement and decreased lever pressing rates. The significance of these findings are discussed in the context of the relationship between the state-dependent effects of BZ-receptor agonists and their other properties, and the receptor subtypes which might underly these effects.