Potency of positive γ-aminobutyric acidA modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys

Lance R. Mcmahon, Lisa R. Gerak, Charles P. France

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

In monkeys discriminating midazolam (0.56 mg/kg s.c.) from saline, substitution for midazolam was elicited by various positive γ-aminobutyric acidA (GABAA) modulators, including the benzodiazepines (BZs) triazolam, midazolam, and diazepam; the BZ1-selective ligands zaleplon and zolpidem; the barbiturates amobarbital and pentobarbital; and the neuroactive steroid pregnanolone. In another group of diazepam (5.6 mg/kg/day p.o.)-treated monkeys discriminating flumazenil (0.32 mg/kg s.c.) from vehicle, these positive GABAA modulators shifted the flumazenil dose-effect function to the right, i.e., attenuated diazepam withdrawal. The potency of positive GABAA modulators to substitute for midazolam in untreated monkeys did not predict their potency to attenuate the flumazenil stimulus in diazepam-treated monkeys. For instance, larger doses of BZs and BZ1-selective ligands were required to attenuate the flumazenil stimulus than to substitute for midazolam. The opposite relationship was revealed for non-BZ ligands, i.e., smaller doses of barbiturates and a neuroactive steroid were required to attenuate the flumazenil stimulus than to substitute for midazolam. The greater potency of non-BZ site ligands to attenuate diazepam withdrawal might be due to actions at a subtype of GABAA receptor not modulated by BZ site ligands, to the development of BZ tolerance without cross-tolerance to non-BZ site ligands, or to noncompetitive interactions at the GABAA receptor complex. Thus, interactions among GABAA modulators in BZ-dependent subjects are not predicted by their acute actions in nondependent subjects. It is not clear whether attenuation of BZ withdrawal is determined by subunit specificity or site of action on the GABAA receptor complex.

Original languageEnglish (US)
Pages (from-to)1227-1235
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume298
Issue number3
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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