Modulation of cocaine and food self-administration by low- and high-efficacy D1 agonists in squirrel monkeys

Abstract.

Rationale: Dopamine D1 ligands have been proposed as candidate medications for cocaine abuse. Previous studies have shown that the ability of D1 ligands to modulate the behavioral effects of cocaine may depend on agonist efficacy. Objectives: This study investigated the role of agonist efficacy in the ability of D1 ligands to modulate the reinforcing effects of cocaine in monkeys. Methods: Squirrel monkeys trained to self-administer cocaine under a second-order schedule of reinforcement were treated daily with D1 agonists varying in efficacy from low to high (SKF 83959 < SKF 77434 ≤ SKF 81297 < SKF 82958) and the D1 antagonist SCH 39166. Results: D1 ligands, regardless of efficacy, produced dose-dependent reductions in responding maintained by a maximally effective dose of cocaine. Equivalent doses of each D1 ligand reduced responding for food under a similar second-order schedule, suggesting that the suppression was not specific to cocaine self-administration. When studied in combination with a range of cocaine doses, treatment with the agonists SKF 83959, SKF 77434, SKF 81297, and the antagonist SCH 39166 produced overall rightward and downward shifts in the dose–response function for cocaine self-administration. Treatment with the agonist SKF 82958, however, produced an overall suppression of responding, regardless of the dose of cocaine. Conclusions: In contrast to a high-efficacy agonist, low-efficacy D1 ligands modulated the reinforcing effects of cocaine in a manner consistent with at least a partial antagonism of cocaine self-administration. This delineation of the efficacy-dependent profile of effects for D1 ligands should guide research into their utility as cocaine pharmacotherapies.