Discriminative stimulus effects of zolpidem in squirrel monkeys: comparison with conventional benzodiazepines and sedative-hypnotics.
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.
Rowlett
J K
JK
Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts 01772-9102, USA.
Spealman
R D
RD
Lelas
S
S
D000818:Animals; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012453:Saimiri; D000077334:Zolpidem
D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D011725:Pyridines; D001569:Benzodiazepines; D005442:Flumazenil; D000077334:Zolpidem; D008874:Midazolam