Acute cross tolerance to midazolam and not pentobarbital and pregnanolone following a single dose of chlordiazepoxide in monkeys discriminating midazolam

摘要

Although cross tolerance can develop among positive GABAA modulators acting at the same modulatory site, cross tolerance does not always develop to drugs acting at sites that are different from the site of action of the drug administered chronically. To examine the relationship between cross tolerance and site of action, four rhesus monkeys discriminated midazolam and, on separate occasions, received 32 mg/kg of chlordiazepoxide 24 hr before dose-effect determinations for drugs acting at different sites. Midazolam, pentobarbital and pregnanolone produced >80% midazolam-lever responding. Although monkeys responded on the midazolam lever 2–4 hr after 32 mg/kg of chlordiazepoxide, they responded on the saline lever 24 hr later. Twenty-four hr after an acute injection of 32 mg/kg of chlordiazepoxide, midazolam dose-effect curves were shifted 4.6-fold to the right whereas pregnanolone dose-effect curves were shifted 3-fold to the left. Sensitivity to pentobarbital increased in one monkey and decreased in others 24 hr after chlordiazepoxide. Decreased sensitivity to midazolam demonstrates that acute cross tolerance develops following chlordiazepoxide administration, although it does not develop to drugs acting at other sites. These differences among positive GABAA modulators suggest that even short-term benzodiazepine administration changes GABAA receptors, and those changes impact modulatory sites differently.