Citation

Lau CE, Ma F, Foster DM, Falk JL. J. Pharmacol. Exp. Ther. 1999; 288(2): 535-543.

Affiliation

Department of Psychology, Rutgers University, Piscataway, New Jersey 08854-8020, USA. clau@rci.rutgers.edu

Copyright

(Copyright © 1999, American Society for Pharmacology and Experimental Therapeutics)

DOI

unavailable

PMID

9918556

Abstract

We investigated dose-response cocaine pharmacokinetic and metabolite profiles in a within-subject design after intravenous bolus cocaine administration (1-4 mg/kg) in rats under a food-limited regimen. Cocaine was rapidly distributed (T1/2beta = 1.09 min) and eliminated (T1/2alpha = 14.93 min). Norcocaine was not detected. The free fraction of cocaine was 31.3-33.1% for serum cocaine concentrations of 0.5 to 1 microg/ml. Parallel pharmacodynamics was studied using performance on a contingency-controlled timing behavior, a differential reinforcement of low rate schedule (45 s) in 3-h sessions. Cocaine increased the shorter-response rate and decreased the density of reinforcement in a dose- and time-related fashion. The increased shorter-response rate is the stimulatory effect herein reported. The changes in shorter-response rate and the density of reinforcement were directly interpretable as functions of cocaine concentrations in the respective hypothetical effect compartments by using sigmoidal Emax and inhibitory Emax models, respectively. Because the concentration at half of Emax for the shorter-response rate (EC50 = 0.467 microg/ml) was greater than that for density of reinforcement (IC50 = 0.070 microg/ml), the former began to return toward baseline sooner than the latter. Only as cocaine concentration decreased to values smaller than the EC50 did the density of reinforcement begin to return toward baseline. Thus, the density of reinforcement is an index for evaluating the deficit in timing performance. The concentration-effect plot confirmed that the intensity of the effects of cocaine depends solely on concentration regardless of the dose. These results demonstrated that the pharmacokinetic-pharmacodynamic analysis allows the identification of the stimulant action of cocaine, which in turn delineates its consequence on timing performance.

Language: en