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.
Lau
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CE
Department of Psychology, Rutgers University, New Brunswick, NJ 08903, USA. clau@rci.rutgers.edu
Wang
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Y
Ma
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F
D000465:Algorithms; D000818:Animals; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003216:Conditioning, Operant / Q000187:drug effects; D006207:Half-Life; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D007202:Indicators and Reagents; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
D000697:Central Nervous System Stimulants; D006993:Hypnotics and Sedatives; D007202:Indicators and Reagents; D008874:Midazolam