Pharmacokinetic-pharmacodynamic modeling of the coexistence of stimulatory and sedative components for midazolam.

Midazolam increased the shorter-response rate and decreased the reinforcement rate of a contingency-controlled timing behavior--a differential-reinforcement-of-low-rate 45-s schedule. The responding rate changes observed were immediately interpretable as functions of midazolam concentration during a 3-h session--a period for investigating the onset, peak, and disappearance of midazolam effect--in rats. That the midazolam pharmacokinetic-pharmacodynamic model was a direct application of our alprazolam pharmacokinetic-pharmacodynamic model implies that both drugs exhibit similar pharmacological effects. The two peaks of the shorter-response rate increases produced by midazolam were modeled as a stimulation-sedation model that consisted of two opposing effect-link sigmoidal Emax functions. The stimulation-sedation model suggested that midazolam possesses both stimulatory and sedative effects in a continuous but sequential fashion, and hypothesizes the coexistence of stimulation and sedation components for midazolam; this model may help delineate possible mechanisms for rebound side effects and of tolerance in humans. The reinforcement rate was, then, an index for evaluating the deficit in timing performance.