Stereoselective discriminative stimulus effects of zopiclone in rhesus monkeys

Lance R. McMahon, Thomas P. Jerussi, Charles P. France

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Rationale: The behavioral effects of racemic zopiclone are similar to those of benzodiazepines that positively modulate GABA at the GABAA receptor complex; however, it is not clear how enantiomers or metabolites of zopiclone contribute to the benzodiazepine-like behavioral effects of racemic zopiclone. Objectives: Racemic zopiclone, its (R)- and (S)- enantiomers, and the (S)-N-desmethyl metabolite, were evaluated for discriminative stimulus effects in untreated and diazepam treated rhesus monkeys. Methods: One group of monkeys discriminated the benzodiazepine midazolam and another group, treated daily with the benzodiazepine diazepam (5.6 mg/kg, PO), discriminated the benzodiazepine antagonist flumazenil. Results: (RS)-Zopiclone (0.32-17.8 mg/kg) and (S)-zopiclone (0.1-10 mg/kg) substituted with similar potencies for midazolam (≤80% midazolam-appropriate responding). The midazolam-like discriminative stimulus effects of (RS)-zopiclone were antagonized by flumazenil (pKB=7.52). (R)-Zopiclone occasioned a maximum 45% midazolam-appropriate responding at a dose of 100 mg/kg; (S)-desmethylzopiclone produced saline-appropriate responding up to a dose of 100 mg/kg. All four test compounds occasioned predominantly vehicle-appropriate responding in diazepam treated monkeys discriminating flumazenil. (RS)-Zopiclone (10 mg/kg) attenuated the discriminative stimulus effects of flumazenil in diazepam treated monkeys. Conclusions: These results clearly demonstrate that in rhesus monkeys the discriminative stimulus effects of zopiclone are stereoselective and qualitatively similar to those of midazolam. These results fail to show any benzodiazepine-like or benzodiazepine antagonist-like discriminative stimulus effects for (S)-N-desmethylzopiclone, suggesting that any behavioral (e.g. anxiolytic) effects of this compound are not the result of actions at benzodiazepine receptors.

Original languageEnglish (US)
Pages (from-to)222-228
Number of pages7
JournalPsychopharmacology
Volume165
Issue number3
DOIs
StatePublished - Jan 2003

Keywords

  • Benzodiazepine
  • Drug discrimination
  • GABA
  • Rhesus monkey
  • Zopiclone

ASJC Scopus subject areas

  • Pharmacology

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