Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA_A/α₁ receptors

Abstract

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 GABA_A/α₁ receptors is not known.

Objectives. The present study investigated the ability of GABA_A/α₁-preferring agonists to substitute for training doses of zolpidem greater than or equal to 3.0 mg/kg and the ability of GABA_A/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 GABA_A/α₁ receptors. Antagonism of the effects of zolpidem was studied using the GABA_A/α₁-preferring antagonists β-carboline-3-carboxylate-t-butyl ester (β-CCT) and 3-propyloxy-β-carboline (3-PBC).

Results. Zolpidem and quazepam (GABA_A/α₁-preferring agonist) engendered full substitution for zolpidem, whereas CL 218,872 (GABA_A/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 GABA_A/α₁ receptors in the discriminative stimulus effects of zolpidem at relatively high training doses, and suggest that selectivity and relatively high efficacy at GABA_A/α₁ receptors is required for BZ agonists to reproduce these discriminative stimulus effects.