Efficacy and the discriminative stimulus effects of negative GABA A modulators, or inverse agonists, in diazepam-treated rhesus monkeys

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

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

In benzodiazepine (BZ)-dependent animals, the effects of negative GABA A modulators at BZ sites are not clearly related to differences in negative efficacy (i.e., inverse agonist activity). A flumazenil discriminative stimulus in diazepam (5.6 mg/kg/day)-treated rhesus monkeys was used to test the hypothesis that the effects of negative GABAA modulators at BZ sites do not vary as a function of efficacy in BZ-dependent animals. Negative GABAA modulators varying in efficacy were studied in combination with positive modulators acting at different modulatory sites (BZ, barbiturate, and neuroactive steroid sites). The negative modulators Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-α]-[1,4] benzodiazepine-3-carboxylate) and ethyl β-carboline-3-carboxylate (β-CCE) substituted for the flumazenil discriminative stimulus. Acute pretreatment with diazepam (3.2 and 10 mg/kg s.c., in addition to 5.6 mg/kg/day p.o.), pentobarbital (3.2 and 10 mg/kg), or pregnanolone (1 and 3.2 mg/kg) attenuated the flumazenil discriminative stimulus and also attenuated the flumazenil-like discriminative stimulus effects of Ro 15-4513 and β-CCE. Attenuation of the discriminative stimulus effects of flumazenil, Ro 15-4513, and β-CCE did not systematically vary as a function of negative efficacy. Compared with their discriminative stimulus effects in untreated monkeys discriminating midazolam, both pregnanolone and pentobarbital were relatively more potent than diazepam in attenuating the discriminative stimulus effects of flumazenil, Ro 15-4513, and β-CCE in diazepam-treated monkeys. These results show that the discriminative stimulus effects of BZ-site neutral and negative modulators are not different in BZ-dependent animals trained to discriminate flumazenil, and extend the results of a previous study showing that positive modulators acting at non-BZ sites are especially potent in attenuating the effects of flumazenil in diazepam-treated monkeys (i.e., diazepam withdrawal).

Original languageEnglish (US)
Pages (from-to)907-913
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume318
Issue number2
DOIs
StatePublished - 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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