Using cocaine and apomorphine self-administration in rats to measure the pharmacokinetics of competitive dopamine receptor antagonists administered by different routes

Cocaine self-administration behavior in rats is explained by a pharmacokinetic/pharmacodynamic interaction model. This self-administration model represents a pharmacological bioassay system that can measure the pharmacokinetics and the pharmacodynamic potency of self-administered stimulants, and also dopamine receptor antagonists. However, the time course of effect of antagonists reflects in part their pharmacodynamic potency, complicating conclusions about their pharmacokinetics. The time course of absorption of drugs is typically different by different routes of administration. This study investigated the time course and magnitude of effect of the D1- and D2- selective antagonists, SCH23390 and (-)Eticlopride respectively, on cocaine and apomorphine self-administration when administered via intravenous, subcutaneous, and intraperitoneal routes. The time course of antagonist effects on both cocaine and apomorphine self-administration were different by the different routes of administration, consistent with different rates of absorption especially by the IP route. However, the area under the time-effect curve were relatively similar indicating that antagonist bioavailability was similar via these different routes. Cocaine and apomorphine self-administration in rats can be used as a pharmacological bioassay system to measure the pharmacokinetics of dopamine receptor antagonists, presumably in the brain, in real time in-vivo. This assay system may provide pharmacokinetic information complimentary to standard timed plasma concentration methods.