Discriminative stimulus effects of benzodiazepine (BZ)(1) receptor-selective ligands in rhesus monkeys.
Drug discrimination was used to examine the effects of benzodiazepine (BZ)(1) receptor-selective ligands in rhesus monkeys. In diazepam-treated (5.6 mg/kg, p.o.) monkeys discriminating the nonselective BZ antagonist flumazenil (0.32 mg/kg, s.c.), the BZ(1)-selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) substituted for flumazenil. The onset of action of beta-CCt was delayed with a dose of 5.6 mg/kg beta-CCt substituting for flumazenil 2 h after injection. In monkeys discriminating the nonselective BZ agonist midazolam (0.56 mg/kg, s.c.), the BZ(1)-selective agonists zaleplon (ED(50) = 0.78 mg/kg) and zolpidem (ED(50) = 1.73 mg/kg) substituted for midazolam. The discriminative stimulus effects of midazolam, zaleplon, and zolpidem were antagonized by beta-CCt (1.0-5.6 mg/kg, s.c.), and the effects of zaleplon and zolpidem were also antagonized by flumazenil (0.01-0.32 mg/kg, s.c.). Schild analyses supported the notion of a simple, competitive interaction between beta-CCt and midazolam (slope = -1.08; apparent pA(2) = 5.41) or zaleplon (slope = -1.57; apparent pA(2) = 5.49) and not between beta-CCt and zolpidem. Schild analyses also were consistent with a simple, competitive interaction between flumazenil and zaleplon (slope = -1.03; apparent pA(2) = 7.45) or zolpidem (slope = -1.11; apparent pA(2) = 7.63). These results suggest that the same BZ receptor subtype(s) mediate(s) the effects of midazolam, zolpidem, and zaleplon under these conditions and that selective binding of BZ ligands does not necessarily confer selective effects in vivo.
McMahon
Lance R
LR
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 78229-3900, USA.
Gerak
Lisa R
LR
Carter
Lawrence
L
Ma
Chunrong
C
Cook
James M
JM
France
Charles P
CP
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008024:Ligands; D008253:Macaca mulatta; D008874:Midazolam / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D000077334:Zolpidem
D000081:Acetamides; D002243:Carbolines; D018755:GABA Agonists; D018756:GABA Antagonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D008024:Ligands; D011725:Pyridines; D011743:Pyrimidines; D011963:Receptors, GABA-A; D005442:Flumazenil; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate; D003975:Diazepam; D008874:Midazolam; C085665:zaleplon