Abstract
The present study examined whether zolpidem, an imidazopyridine with selectivity for benzodiazepine (BZ)/γ-aminobutyric acidAreceptors containing the α1-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 α1-subunit of the BZ/γ-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.
Footnotes
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Send reprint requests to: James K. Rowlett, Ph.D., Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Dr., Box 9102, Southborough, MA 01772-9102.
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↵1 This research was supported by U.S. Public Health Service Grants DA11792 and RR00168.
- Abbreviations:
- BZ
- benzodiazepine
- GABA
- γ-aminobutyric acid
- DS
- discriminative stimulus
- FR
- fixed ratio
- 5-HT
- 5-hydroxytryptamine
- CI
- confidence interval
- SEC
- standard error of the coefficient
- Received June 29, 1999.
- Accepted September 7, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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