Analysis of the role of behavioural factors in the development of tolerance to the benzodiazepine midazolam.

Two experiments were conducted on the acute and chronic effects of the short-acting benzodiazepine midazolam on fixed ratio schedule-maintained operant responding in rats. Acute administration of midazolam produced suppression of responding in large doses but elevation of responding in small doses. Following intermittent (every third day) chronic treatment tolerance developed rapidly to the rate-suppressant effects of large doses of midazolam but did not develop to the rate-elevating effects of small doses, even after chronic treatment with large doses of the drug. Thus, when tolerance was measured in terms of shifts in dose-effect curves, it was manifested as a non-parallel shift in the curve after chronic treatment. Since tolerance developed to the effects of large but not small doses, the observed tolerance could not be attributed to changes in disposition of the drug. The development of tolerance did not depend on whether the drug was given before or after behavioural testing. These findings contrast with data reported in behavioural studies with other sedative-hypnotics (ethanol, barbiturates). Animals tolerant to midazolam showed no cross-tolerance to ethanol, a drug for which there is reliable evidence indicating that behavioural factors play a role in acquisition of tolerance. Tolerance to midazolam cannot therefore be explained in terms of learned strategies acquired as a result of drug-induced loss of rewarding stimuli. This conclusion contrasts with recent suggestions (File, 1985; File and Pellow, 1985) that tolerance to benzodiazepines may be mediated by instrumental conditioning processes.