Investigation of the development of tolerance to the actions of zolpidem and midazolam.

It is well established that tolerance can develop very rapidly to the behaviour-suppressing effects of benzodiazepines. In previous studies, however, the depressant action of zolpidem, a novel hypnotic acting at the benzodiazepine receptor, on operant behaviour in rats was maintained after many injections. An experiment was carried out, therefore, to compare the effects of acute and chronic administration of zolpidem and midazolam. Rats were trained to press a lever in standard operant test chambers to obtain 45 mg food pellets on an FR 10 schedule. Dose-response curves were then established, before, immediately after and 4 weeks after the daily administration of midazolam (3.0 mg/kg s.c.) or zolpidem (1.0 mg/kg) for 10 days. In confirmation of previous work, marked tolerance developed to the response-rate-decreasing effect of midazolam, the dose-response curve being shifted to the right by a factor of 6 and also flattened. No significant dissipation of this tolerance occurred during a period of 4-6 weeks. In contrast, repeated administration of zolpidem produced only a small degree of tolerance, the dose-response curve being shifted by a factor of two. There was little evidence for cross tolerance between the two drugs, zolpidem-treated rats being sensitive to a dose of midazolam and midazolam-treated rats sensitive to a dose of zolpidem. Although the explanation for the development of tolerance to midazolam is unknown, these results suggest that the mechanisms of action of midazolam and zolpidem in reducing response rates are different.