The affinity of D2-like dopamine receptor antagonists determines the time to maximal effect on cocaine self-administration

Abstract

Differences in the time to maximal effect (T(max)) of a series of dopamine receptor antagonists on the self-administration of cocaine are not consistent with their lipophilicity (octanol-water partition coefficients at pH 7.4) and expected rapid entry into the brain after intravenous injection. It was hypothesized that the T(max) reflects the time required for maximal occupancy of receptors, which would occur as equilibrium was approached. If so, the T(max) should be related to the affinity for the relevant receptor population. This hypothesis was tested using a series of nine antagonists having a 2500-fold range of K(i) or K(d) values for D(2)-like dopamine receptors. Rats self-administered cocaine at regular intervals and then were injected intravenously with a dose of antagonist, and the self-administration of cocaine was continued for 6 to 10 h. The level of cocaine at the time of every self-administration (satiety threshold) was calculated throughout the session. The satiety threshold was stable before the injection of antagonist and then increased approximately 3-fold over the baseline value at doses of antagonists selected to produce this approximately equivalent maximal magnitude of effect (maximum increase in the equiactive cocaine concentration, satiety threshold; C(max)). Despite the similar C(max), the mean T(max) varied between 5 and 157 min across this series of antagonists. Furthermore, there was a strong and significant correlation between the in vivo T(max) values for each antagonist and the affinity for D(2)-like dopamine receptors measured in vitro. It is concluded that the cocaine self-administration paradigm offers a reliable and predictive bioassay for measuring the affinity of a competitive antagonist for D(2)-like dopamine receptors.