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


OBJECTIVE
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.
Rowlett
James K
JK
Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102, USA. james_rowlett@hms.harvard.edu
Spealman
Roger D
RD
Lelas
Snjezana
S
Cook
James M
JM
Yin
Wenyuan
W
D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001569:Benzodiazepines; D002243:Carbolines / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005445:Flunitrazepam / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D007275:Injections, Intravenous; D008297:Male; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000502:physiology*; D012453:Saimiri; D000077334:Zolpidem
C454686:3-propoxy-beta-carboline; D014151:Anti-Anxiety Agents; D002243:Carbolines; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D011724:Pyridazines; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005445:Flunitrazepam; C021604:CL 218872; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate; C025130:quazepam; D000525:Alprazolam