Interactions of cocaine with dopamine D₂-like antagonists in squirrel monkeys

Rationale: Studies investigating dopamine D₂ receptor antagonism of cocaine's discriminative stimulus effects have resulted in varied effects possibly due to the use of different antagonists, species, and procedures. Objectives: The present study sought to further investigate D₂ antagonism of cocaine's discriminative stimulus effects using a variety of D₂ antagonists and multiple doses of the antagonists in combination with cocaine. Methods: The benzamide D₂ antagonists, eticlopride, raclopride, and sulpiride, and the butyrophenone D₂ antagonists haloperidol and spiperone were administered alone and in combination with cocaine in squirrel monkeys trained to discriminate cocaine from saline under a fixed-ratio food reinforcement procedure. Results: All the D₂ antagonists, except haloperidol, antagonized the discriminative stimulus effects of the cocaine training dose. However, only the benzamide D₂ antagonists produced significant rightward shifts in the cocaine discriminative stimulus dose-effect curve and they only did so within a narrow dose range and time after administration. In contrast, the D₂ antagonists failed to antagonize the rate-suppressant effects of cocaine, and in some cases, cocaine appeared to antagonize the rate-suppressant effects of the antagonists. Conclusions: The present results suggest (1) that D₂ antagonism of cocaine's discriminative stimulus effects depends critically on the selected antagonist, antagonist dose, and time of administration, as well as how antagonism is assessed (i.e., in terms of effects on training dose or on the cocaine dose-effect curve), (2) that the maximal shift in cocaine's discriminative stimulus dose-effect curve possible with D₂ antagonists under these procedures is ~two- to threefold, and (3) that different effects of cocaine are differentially sensitive to dopamine receptor antagonism.