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, Charles P. France

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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 β-carboline-3-carboxylate-t-butyl ester (β-CCt) substituted for flumazenil. The onset of action of β-CCt was delayed with a dose of 5.6 mg/kg β-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 β-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 β-CCt and midazolam (slope = -1.03; apparent pA2 = 5.41) or zaleplon (slope = -1.57; apparent pA2 = 5.49) and not between β-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.

Original languageEnglish (US)
Pages (from-to)505-512
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume300
Issue number2
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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