Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABAA/α1 receptors
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Rationale. The discriminative stimulus effects of zolpidem in squirrel monkeys trained at doses greater than or equal to 3.0 mg/kg differ from those of conventional benzodiazepines (BZs), but the extent to which these effects reflect the selectivity of zolpidem for GABAA/α1 receptors is not known.
Objectives. The present study investigated the ability of GABAA/α1-preferring agonists to substitute for training doses of zolpidem greater than or equal to 3.0 mg/kg and the ability of GABAA/α1-preferring antagonists to block zolpidem's discriminative stimulus effects.
Methods. Squirrel monkeys were trained to discriminate intravenous injections of zolpidem (3.0 or 5.6 mg/kg) from saline and tested with BZ agonists differing in selectivity and efficacy at GABAA/α1 receptors. Antagonism of the effects of zolpidem was studied using the GABAA/α1-preferring antagonists β-carboline-3-carboxylate-t-butyl ester (β-CCT) and 3-propyloxy-β-carboline (3-PBC).
Results. Zolpidem and quazepam (GABAA/α1-preferring agonist) engendered full substitution for zolpidem, whereas CL 218,872 (GABAA/α1-preferring partial agonist) and the non-selective BZ agonists alprazolam and flunitrazepam engendered low and variable levels of zolpidem-lever responding (35–58%). Both β-CCT and 3-PBC antagonized the discriminative stimulus effects of zolpidem in a surmountable fashion.
Conclusions. Our findings provide evidence for a key role of GABAA/α1 receptors in the discriminative stimulus effects of zolpidem at relatively high training doses, and suggest that selectivity and relatively high efficacy at GABAA/α1 receptors is required for BZ agonists to reproduce these discriminative stimulus effects.
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