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 (T_1/2β = 1.09 min) and eliminated (T_1/2α = 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 μg/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 E_maxand inhibitory E_max models, respectively. Because the concentration at half of E_maxfor the shorter-response rate (EC₅₀ = 0.467 μg/ml) was greater than that for density of reinforcement (IC₅₀ = 0.070 μg/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.