Post-injection delays in experimental chambers, but not in home cages, produce both sensitization and tolerance of operant behaviour to midazolam: relation to pharmacokinetics

Abstract

The effects of post-injection delay time and environmental context on behaviour after subcutaneous administration of 3 mg/kg midazolam were investigated under a differential reinforcement of low rate schedule (i.e. DRL 45 s) in 3 h sessions. Post-injection delays were varied (0-120 min) for two groups of rats placed in either the experimental chamber (group 1) or home cage (group 2) during the pre-session delay times. Midazolam increased shorter-response (inter-response times < 45 s) rates and decreased reinforcement rates in a time-related manner. Reinforcement rate-time profiles were also integrated with parallel pharmacokinetics. Post-injection delays in either environment yielded performances that mirrored the pharmacokinetic profile operative at the corresponding time-delay points. At higher concentrations (> 0.12 microg/ml) the pharmacokinetics of midazolam largely determined the behavioural effects in both groups, regardless of post-injection delays. However, at lower drug concentrations, longer post-injection delays (> 60 min) in the experimental chamber produced both sensitization and tolerance, as measured by greater increases in shorter-response rates and a more rapid return of the reinforcement rate, respectively. Interaction of the discriminative stimulus effects of midazolam with the context probably alters the magnitude of behavioural effects when the delay occurs in the experimental chambers, whereas no such interaction is present in group 2. The DRL schedule with post-injection delays in experimental chambers provides a useful behavioural paradigm for studying both sensitization and tolerance.