The role of classical conditioning processes in the development of tolerance to the hypothermic effects of the short-acting benzodiazepine midazolam was studied in three experiments in rats. The experiments were all designed so that one set of environmental stimuli reliably predicted drug treatments whilst another set of stimuli predicted control (vehicle) treatment. According to the classical conditioning account of tolerance, the degree of tolerance observed should be greater in the presence of drug-predictive stimuli than in their absence, i.e. tolerance should show environmental (context) specificity. A preliminary study was conducted to determine the dose-and time-effect curves for midazolam-induced hypothermia. The results of this study provided essential background data for the design of all the subsequent tolerance studies. In the first tolerance study, it was found that virtually complete tolerance developed to the hypothermic effects of 4 mg/kg (IP) midazolam given on alternate days. However, the observed tolerance was clearly not environmentally specific. Since there is evidence that conditioned tolerance to some drug effects develops most readily if drugs are given at low doses with long inter-injection intervals, a second study was conducted with a lower (1.6 mg/kg IP) dose of midazolam, which was given every 5th day. Despite these procedural changes, the second study indicated that the observed tolerance again did not show context specificity, even though tolerance developed rapidly with the lower dose of a short acting drug which was given infrequently. In a final study, the experimental procedure was changed again so that the environmental stimuli which predicted drug treatment were only present during the onset of drug-induced hypothermia, in contrast to the procedure adopted in the two previous studies in which the drug-predictive stimuli were present during the onset and the offset of the drug's hypothermic effect. This procedural change was introduced because it was considered possible that the presence of stimuli associated with recovery from the drug's effects might have prevented the development of conditioned tolerance in the first two studies. However, no evidence was obtained for context specific tolerance, even after this further procedural manipulation. These data indicate clearly that it is difficult to demon-* An abstract report of some of the data presented in this paper has already been published (Goudie and Griffiths 1985).
Offprint requests to : A.J. Goudie strate context specificity of midazolam hypothermic tolerance. A number of possible reasons for these results are considered.