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Antagonism of benzodiazepines by flumazenil in rats discriminating midazolam: Schild analyses
Author(s) -
Gerak Lisa R
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.743.1
Subject(s) - flumazenil , flunitrazepam , pregnanolone , pharmacology , stimulus control , midazolam , benzodiazepine , neuroactive steroid , triazolam , chemistry , gabaa receptor , alprazolam , receptor , medicine , sedation , anxiety , psychiatry , nicotine
The pharmacological selectivity of drug discrimination experiments is often exploited to determine mechanism of action of drugs; however, some classes of drugs, such as positive GABA A modulators, have similar discriminative stimulus effects despite actions at distinct sites. By studying drugs in combination and using quantitative pharmacological analyses, actions at different modulatory sites on GABA A receptors can be elucidated. In the current study, the ability of flumazenil to attenuate the discriminative stimulus effects of the benzodiazepines midazolam and flunitrazepam and the neuroactive steroid pregnanolone was studied in 6 rats discriminating midazolam. Midazolam, flunitrazepam and pregnanolone produced >80% midazolam‐lever responding; flumazenil dose‐dependently antagonized the effects of flunitrazepam and midazolam. Schild analyses for flumazenil studied in combination with flunitrazepam yielded a slope that did not deviate from unity and a pA2 value of 5.87. A dose of 5.6 mg/kg flumazenil, which shifted the flunitrazepam dose‐effect curve 30‐fold to the right, did not attenuate the discriminative stimulus effects of pregnanolone. Because these data conform to theory in a quantifiable manner, drug combination studies in rats can be used to further evaluate interactions between drugs acting at different sites on GABA A receptors. Supported by USPHS grant DA09157.