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

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Abstract

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.

Introduction

Differential-reinforcement-of-low-rate schedules (e.g., 45-s) produce low rates of responding, as only those responses that occur after a minimum time interval (≥45 s) following a previous response are reinforced. Responses that occur before this time elapse are not reinforced, and they reset the timing of the interval. Differential-reinforcement-of-low-rate performance satisfies many of the criteria (i.e., objective, continuous, sensitive and reproducible) proposed as ideal for pharmacodynamic measurement (Dingemanse et al., 1988; Laurijssens and Greenblatt, 1996). In addition, after the drug is administered, one can use reinforced and nonreinforced responses—which generally exhibit decreases and increases, respectively—to evaluate the drug effects. Midazolam is a potent benzodiazepine derivative with sedative, hypnotic, anticonvulsant, muscle-relaxant and anxiolytic activities (Pier et al., 1981). In past research, we found that the differential-reinforcement-of-low-rate 45-s performance largely corresponded to its respective pharmacokinetics after drug administration (Lau and Wang, 1996; Lau et al., 1997a). For example, we used both pharmacokinetics and the effects of midazolam on DRL 45-s performance to clarify that the subcutaneous (s.c.), as opposed to the intraperitoneal (i.p.) route, is the route of choice for the evaluation of midazolam dose-response relations (Lau et al., 1996).

Despite the wide use of midazolam in animal behavioral research (e.g., operant behavior, drug discrimination), pharmacokinetic–pharmacodynamic modeling is rarely performed. We proposed an integrated pharmacokinetic–pharmacodynamic model for alprazolam in order to describe and to predict the time course profiles for serum alprazolam concentration, the reinforcement rate, and the shorter-response (nonreinforced) rate in a previous study (Lau and Heatherington, 1997). The comprehensive pharmacokinetic–pharmacodynamic model also described the interplay between the two rates of responding. We used two sigmoidal Emax models having actions opposite in direction to account for the observed shorter-response rate increases and an indirect response model to describe the reinforcement rate changes. The model suggested that alprazolam possesses both stimulatory and sedative effects in a continuous but sequential fashion—the stimulatory effect preceded the sedative effect and the former lasted longer than the latter. As a result, the reinforcement rate was an index of the timing performance deficits. Some behavioral effects of benzodiazepines were readily evident as characteristics of the coexistence of both stimulatory and sedative effects for alprazolam proposed by the model; no other mechanism has been proposed for these observations. For example, following chronic benzodiazepine administration, tolerance develops rapidly to the sedative or depressant effect of high doses, but it does not develop to the stimulatory effect of low doses (File and Pellow, 1985; Griffiths and Goudie, 1987; Flaherty et al., 1996). In addition, repeated low-dose administration can even enhance the stimulatory effect (Sansone, 1979). If, indeed, stimulatory and sedative effects were continuous—and exhibited a sigmoidal Emax function—but were opposed components, then stimulation would be evident and would become enhanced if tolerance to sedation developed progressively.

One of the aims of the present study was to investigate s.c. midazolam dose-response relations in an ascending and a descending order in 3-h sessions under the differential-reinforcement-of-low-rate 45-s schedule to examine whether the size of the preceding dose affected the response of the subsequent dose when the doses were separated by 3–5 days. We used both reinforced and nonreinforced (i.e., shorter) responses to evaluate the effects of midazolam. The second aim was to characterize midazolam concentration-effect relations in vivo using the above-mentioned alprazolam pharmacokinetic–pharmacodynamic model to investigate whether the model was prototypical for benzodiazepines and can be generalized to midazolam. The implications of this model for adverse side effects noted in humans after benzodiazepine administration will be presented in Section 4.

Section snippets

Animals

Four male, albino, virus free Sprague–Dawley rats (HSD, Indianapolis, IN) with a mean initial body weight of 385 g (range 383–388 g; approximately 80 days old) were used. They were housed individually in a temperature-regulated room with a daily cycle of illumination from 7:00 a.m. to 7:00 p.m. They were reduced to 80% of their initial, adult free-feeding body weights by receiving limited daily food rations (5 g for the first day, 10 g for the next 5 days) and were then maintained at their 80%

Effects of midazolam on differential-reinforcement-of-low-rate performance

Fig. 3A,B show the effects of midazolam on inter-response time distributions for the 3-h sessions. Midazolam shifted the inter-response time distributions in a dose-related fashion; it increased the shorter inter-response times (<45 s) and decreased the reinforced inter-response times (≥45 s). However, the long inter-response times (70–79.9 s) in the reinforced bins increased with each dose. Following the ascending and descending midazolam dosing series, the inter-response time distributions

Discussion

The two measures of differential-reinforcement-of-low-rate 45-s performance, the shorter-response rate and the reinforcement rate, exhibited time- and dose-related changes which were readily interpretable as functions of serum midazolam concentration during 3-h sessions. The stimulation-sedation model and effect-link model presented describe and predict the shorter-response and reinforcement rate changes, respectively. We used one measure of differential-reinforcement-of-low-rate 45-s

Acknowledgements

This research was supported by Grant R37 DA 03117, awarded to J.L. Falk, from the National Institute on Drug Abuse, USA. We thank Dr. Peter F. Sorter of Hoffmann-La Roche, Nutley, NJ, for generously supplying midazolam maleate and its metabolites.

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