Differences in the time to maximum effect (Tmax) of a series of dopamine receptor antagonists on the self-administration of cocaine is not consistent with their lipophilicity (octanol-water partition coefficients at pH 7.4) and expected rapid entry into the brain after i.v. injection. It was hypothesized that the Tmax reflects the time required for maximal occupancy of receptors, which would occur as equilibrium was approached. If so, the Tmax should be related to the affinity for the relevant receptor population. This hypothesis was tested using a series of nine antagonists having a 2,500-fold range of Kd values for D2-like dopamine receptors. Rats self-administered cocaine at regular intervals and then were injected i.v. with a dose of antagonist and the self-administration of cocaine continued for 6-10 hours. The level of cocaine at the time of every self-administration (satiety threshold) was calculated throughout the session. The satiety threshold was stable prior to the injection of antagonist and then increased approximately three-fold over the baseline value at doses of antagonists selected to produce this approximately equivalent maximum magnitude of effect (Cmax). Despite the similar Cmax the mean Tmax varied between 5 min and 157 min across this series of antagonists. Furthermore, there was an excellent and significant inverse correlation between the in vivo Tmax for each antagonist and the Kd value 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.
- Received April 21, 2011.
- Revision received May 19, 2011.
- Accepted May 19, 2011.
- The American Society for Pharmacology and Experimental Therapeutics