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Stereoselective discriminative stimulus effects of zopiclone in rhesus monkeys.

Abstract：

RATIONALE:The behavioral effects of racemic zopiclone are similar to those of benzodiazepines that positively modulate GABA at the GABA(A) 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 (p K(B)=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.

journal_name

Psychopharmacology (Berl)

journal_title

Psychopharmacology

authors

McMahon LR,Jerussi TP,France CP

doi

10.1007/s00213-002-1286-9

subject

Has Abstract

pub_date

2003-01-01 00:00:00

pages

222-8

issue

3

eissn

0033-3158

issn

1432-2072

journal_volume

165

pub_type

杂志文章

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