Discriminative stimulus effects of zolpidem in squirrel monkeys: comparison with conventional benzodiazepines and sedative-hypnotics

J Pharmacol Exp Ther. 1999 Dec;291(3):1233-41.

Abstract

The present study examined whether zolpidem, an imidazopyridine with selectivity for benzodiazepine (BZ)/gamma-aminobutyric acid(A) receptors containing the alpha1-subunit, had discriminative stimulus effects similar to typical BZs and other sedative/hypnotic drugs in primates. Squirrel monkeys (Saimiri sciureus) were trained to discriminate zolpidem (1.0 mg/kg i.v.) from vehicle under a 10-response fixed-ratio schedule of food delivery. Under test conditions, zolpidem (0.1-3.0 mg/kg) increased responding on the drug lever to an average maximum of 90% of total responding. When pretreatment times were varied from 5 to 50 min, the discriminative stimulus effects of zolpidem were maximal at 5 min and near control levels 35 min after administration. Flumazenil antagonized both the discriminative stimulus and rate-decreasing effects of zolpidem in a dose-dependent and surmountable fashion (in vivo apparent pA(2) values of 7.3 and 6.6 for the discriminative stimulus and rate-suppressing effects, respectively). The BZs triazolam, midazolam, diazepam, and N-desmethyldiazepam engendered dose-related increases in drug-lever responding that reached zolpidem-like levels (90%) in the majority of monkeys tested. In contrast, lorazepam, chlordiazepoxide, and oxazepam engendered average maximums of 70% or less and substituted fully for zolpidem in one or two monkeys only. Representative barbiturates as well as drugs that bind to non-BZ sites (muscimol, baclofen, buspirone, cyproheptadine, diphenhydramine) engendered 0 to 45% of responses on the drug lever up to doses that markedly reduced response rate. These results support the view that zolpidem's selectivity for the alpha1-subunit of the BZ/gamma-aminobutyric acid(A) receptor complex confers a distinctive profile of interoceptive effects that overlaps partially with those of typical BZs but not with those of barbiturates.

Publication types

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

MeSH terms

  • Animals
  • Benzodiazepines / antagonists & inhibitors
  • Benzodiazepines / pharmacology*
  • Discrimination, Psychological / drug effects*
  • Dose-Response Relationship, Drug
  • Flumazenil / pharmacology
  • GABA Modulators / pharmacology
  • GABA-A Receptor Agonists
  • Hypnotics and Sedatives / antagonists & inhibitors
  • Hypnotics and Sedatives / pharmacology*
  • Male
  • Midazolam / pharmacology
  • Pyridines / antagonists & inhibitors
  • Pyridines / pharmacology*
  • Saimiri
  • Zolpidem

Substances

  • GABA Modulators
  • GABA-A Receptor Agonists
  • Hypnotics and Sedatives
  • Pyridines
  • Benzodiazepines
  • Flumazenil
  • Zolpidem
  • Midazolam