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Vol. 291, Issue 3, 1233-1241, December 1999

Discriminative Stimulus Effects of Zolpidem in Squirrel Monkeys: Comparison with Conventional Benzodiazepines and Sedative-Hypnotics1

James K. Rowlett, Roger D. Spealman and Snjezana Lelas

Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts

The present study examined whether zolpidem, an imidazopyridine with selectivity for benzodiazepine (BZ)/gamma -aminobutyric acidA receptors containing the alpha 1-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 pA2 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 alpha 1-subunit of the BZ/gamma -aminobutyric acidA receptor complex confers a distinctive profile of interoceptive effects that overlaps partially with those of typical BZs but not with those of barbiturates.

0022-3565/99/2913-1233$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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