Effects of dopamine D_1-like and D_2-like agonists on cocaine self-administration in rhesus monkeys: rapid assessment of cocaine dose-effect functions

Abstract 

Rationale: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D_1-like and D_2-like receptor mechanisms may be involved, recent studies suggest that D_1-like and D_2-like agonists have differing profiles of cocaine-related actions. Objective: To develop a procedure for rapid assessment of complete dose–effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D_1-like and D_2-like agonists on cocaine self-administration using this procedure. Methods: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D_1-like and D_2-like agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. Results: Complete inverted U-shaped dose–effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose– effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D_1-like agonists SKF 82958 (0.32–1.8 mg/kg) and R-6-Br-APB (0.1–1.0 mg/kg) produced downward shifts in the cocaine dose–effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D_2-like agonists quinelorane (0.001–0.01 mg/kg) and 7-OH-DPAT (0.01–0.10 mg/kg) shifted the cocaine dose–effect function to the left. D_2-like agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. Conclusions: The results suggest that D_1-like and D_2-like agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.