The pharmacodynamic and pharmacokinetic potencies of receptor antagonists measured using the drug self-administration assay

Andrew Norman, Vladimir Tsibulsky
University of Cincinnati, Cincinnati, Ohio, United States

A pharmacokinetic (PK)/pharmacodynamic (PD) model of cocaine self-administration demonstrated that when cocaine concentrations were above a minimum maintained level, termed the satiety threshold (Dst), the time between self-injections (T) will be described by the equation: T = ln(1 + Du/Dst).t1/2/ln(2), where Du is the unit dose and t1/2 is the elimination half-life of cocaine (Tsibulsky and Norman, 1999). Therefore, the concentration of cocaine is a critical determinant of the probability of self-administration. According to pharmacological theory, competitive antagonists increase the concentration of agonist required to produce a defined magnitude of response, which in this model is the satiety threshold. The magnitude of the increase in satiety threshold as a function of antagonist dose would reflect the PD potency of the antagonist in vivo, while the time course of the effect would reflect the antagonist PK.

Male Sprague-Dawley rats (385-536 g over the course of the study) were trained to self-administer the indirect and direct agonists cocaine and apomorphine, respectively, with unrestricted access. During daily sessions, once a stable rate of self-administration was established at a unit dose of 150 or 3000 nmol/kg for apomorphine or cocaine, respectively, an i.v. dose of between 5 and 30 nmol/kg of either the D1 or the D2 dopamine receptor antagonists SCH23390 or (-)eticlopride was rapidly administered and the session continued.

The antagonists accelerated the rate of drug self-administration, which gradually returned towards baseline values over the subsequent 3-5 hours. 8 The calculated agonist level at the time of each lever press (satiety threshold) rapidly increased and then gradually decreased over time. The magnitude of the maximal increase in the satiety threshold was proportional to the dose of antagonist. For the direct agonist, apomorphine, the intercept of a plot of the agonist dose ratio as a function of the antagonist dose according to the method of Schild should, assuming equilibrium conditions, represent the dose of antagonist that results in 50% fractional occupancy of the receptors underlying the satiety response. This constant (Kdose) represents the product of the antagonist affinity constant (Kd) and its volume of distribution. The slopes of the plots were 1.2 and 1.3 and the Kdose was 9 and 7 nmol/kg for eticlopride and SCH23390, respectively. Interestingly, although cocaine is an indirect agonist, for these antagonists the slopes of the plots were 1.1 and 1.0. The Kdose was 12 and 8 nmol/kg, respectively. The calculated t1/2 values for the effect compartment for both antagonists were approximately 40–50 min. The t1/2s were independent of the dose of each antagonist and independent of the self-administered drug.

The low antagonist Kdose values are consistent with both D1- and D2-like dopamine receptors mediating the satiety response in rats and the similarity of the Kdose values across agonists indicate that the same receptors mediate the satiety response for cocaine and apomorphine. The time course of the change in the magnitude of the satiety threshold also represents a novel in vivo assay system to measure the PK of antagonists of the receptors underlying the satiety response. This assay system requires no blood samples or analytical chemistry and small quantities of antagonists, reflects antagonist concentrations at the active site in the brain rather than in plasma and is potentially sensitive to active metabolites of the antagonists.

Tsibulsky VL, Norman AB (1999). Brain Res 839:85-93