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Decreased sensitivity to midazolam and not pentobarbital or pregnanolone following acute chlordiazepoxide administration in monkeys discriminating midazolam
Author(s) -
Gerak Lisa R,
McMahon Lance R,
France Charles P
Publication year - 2006
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.20.4.a235-c
Subject(s) - midazolam , chlordiazepoxide , pregnanolone , pentobarbital , gabaa receptor , pharmacology , triazolam , benzodiazepine , flumazenil , cross tolerance , hypnotic , stimulus control , anesthesia , medicine , diazepam , receptor , neuroactive steroid , morphine , sedation , nicotine
Although cross tolerance can develop among positive modulators that act at a single modulatory site on GABAA receptors, cross tolerance may not develop to drugs acting at modulatory sites that are different from the site of action of the drug administered chronically. To determine whether sensitivity to positive GABAA modulators is altered differentially depending on site of action, 4 rhesus monkeys discriminated midazolam and received 32 mg/kg of chlordiazepoxide (CDP) acutely; on separate occasions, sensitivity to drugs acting at different modulatory sites was examined. Midazolam, pentobarbital and pregnanolone produced >80% responding on the midazolam lever. Monkeys responded on the saline lever 24 hr after receiving CDP; under that condition, the dose‐effect curve for midazolam was shifted 3‐fold to the right of the control dose‐effect curve. In contrast, sensitivity to pregnanolone and pentobarbital was not decreased 24 hr after CDP administration. Thus, decreased sensitivity to midazolam suggests that acute cross tolerance developed. Despite similarities in the discriminative stimulus effects of drugs that act at different modulatory sites on GABAA receptors, the differential development of acute cross tolerance indicates that drugs acting at different modulatory sites are not identical; these differences could be beneficial for patients who are treated daily with positive GABAA modulators. Supported by USPHS grants DA09157 and DA017240 and a Senior Scientist Award to CPF (DA17918).