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 D₂-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 D₂-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 D₂-like dopamine receptors.