Vol. 300, Issue 2, 505-512, February 2002

Discriminative Stimulus Effects of Benzodiazepine (BZ)₁ Receptor-Selective Ligands in Rhesus Monkeys

Lance R. McMahon, Lisa R. Gerak, Lawrence Carter, Chunrong Ma, James M. Cook and Charles P. France

Departments of Pharmacology (L.R.M., C.P.F.) and Psychiatry (C.P.F.), The University of Texas Health Science Center at San Antonio, San Antonio, Texas; Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana (L.R.G.); and Department of Chemistry, University of Wisconsin at Milwaukee, Milwaukee, Wisconsin (C.M., J.M.C.)

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 BZ₁-selective antagonist -carboline-3-carboxylate-t-butyl ester (-CCt) substituted for flumazenil. The onset of action of -CCt was delayed with a dose of 5.6 mg/kg -CCt substituting for flumazenil 2 h after injection. In monkeys discriminating the nonselective BZ agonist midazolam (0.56 mg/kg, s.c.), the BZ₁-selective agonists zaleplon (ED₅₀ = 0.78 mg/kg) and zolpidem (ED₅₀ = 1.73 mg/kg) substituted for midazolam. The discriminative stimulus effects of midazolam, zaleplon, and zolpidem were antagonized by -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 -CCt and midazolam (slope = 1.08; apparent pA₂ = 5.41) or zaleplon (slope = 1.57; apparent pA₂ = 5.49) and not between -CCt and zolpidem. Schild analyses also were consistent with a simple, competitive interaction between flumazenil and zaleplon (slope = 1.03; apparent pA₂ = 7.45) or zolpidem (slope = 1.11; apparent pA₂ = 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.