Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA(A)/alpha1 receptors

Psychopharmacology (Berl). 2003 Jan;165(3):209-15. doi: 10.1007/s00213-002-1275-z. Epub 2002 Nov 6.


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)/alpha(1) receptors is not known.

Objectives: The present study investigated the ability of GABA(A)/alpha(1)-preferring agonists to substitute for training doses of zolpidem greater than or equal to 3.0 mg/kg and the ability of GABA(A)/alpha(1)-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)/alpha(1) receptors. Antagonism of the effects of zolpidem was studied using the GABA(A)/alpha(1)-preferring antagonists beta-carboline-3-carboxylate-t-butyl ester (beta-CCT) and 3-propyloxy-beta-carboline (3-PBC).

Results: Zolpidem and quazepam (GABA(A)/alpha(1)-preferring agonist) engendered full substitution for zolpidem, whereas CL 218,872 (GABA(A)/alpha(1)-preferring partial agonist) and the non-selective BZ agonists alprazolam and flunitrazepam engendered low and variable levels of zolpidem-lever responding (35-58%). Both beta-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)/alpha(1) receptors in the discriminative stimulus effects of zolpidem at relatively high training doses, and suggest that selectivity and relatively high efficacy at GABA(A)/alpha(1) receptors is required for BZ agonists to reproduce these discriminative stimulus effects.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alprazolam / pharmacology
  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Benzodiazepines*
  • Carbolines / pharmacology
  • Discrimination Learning / drug effects*
  • Discrimination Learning / physiology
  • Dose-Response Relationship, Drug
  • Flunitrazepam / pharmacology
  • GABA Agonists / pharmacology*
  • GABA Antagonists / pharmacology
  • GABA-A Receptor Agonists
  • Injections, Intravenous
  • Male
  • Pyridazines / pharmacology
  • Pyridines / pharmacology*
  • Receptors, GABA-A / physiology*
  • Saimiri
  • Zolpidem


  • 3-propoxy-beta-carboline
  • Anti-Anxiety Agents
  • Carbolines
  • GABA Agonists
  • GABA Antagonists
  • GABA-A Receptor Agonists
  • Pyridazines
  • Pyridines
  • Receptors, GABA-A
  • Benzodiazepines
  • Flunitrazepam
  • CL 218872
  • Zolpidem
  • tert-butyl beta-carboline-3-carboxylate
  • quazepam
  • Alprazolam