Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats

Abstract

A procedure is described for comprehensive evaluation of the effects of acute drug pretreatments on the reinforcing effects of cocaine using the rat self-administration assay in combination with a novel control assay of liquid-food maintained responding. In sessions comprised of five 20-min components, either complete dose-effect functions for cocaine self-administration or complete concentration-effect functions for liquid-food maintained responding were evaluated. The schedule of reinforcement (FR 5 TO 20-s), drug pretreatment doses and time intervals (0-30 min), and duration of sessions (108 min) were identical for cocaine- and food-reinforced test sessions. Whereas acute pretreatment with indirect dopamine agonists (D-amphetamine, GBR 12909) and D2-like agonists (7-OH-DPAT, quinelorane) produced dose-dependent leftward shifts in dose-effect functions for cocaine self-administration, D1-like agonists (SKF 82958, R-6-Br-APB) and dopamine antagonists (D1-like, SCH 39166; D2-like, eticlopride) shifted dose-effect functions for cocaine downward and rightward, respectively. Interestingly, with the indirect dopamine agonists but not the D2-like agonists, increased responding maintained by low cocaine doses was paralleled by increased responding maintained by low food concentrations. Moreover, three of the four direct agonists were moderately selective (< or =5-fold more potent) in decreasing cocaine self-administration relative to food maintained responding. When data were analyzed according to alterations in total cocaine intake, all of the agonists uniformly decreased total cocaine intake, whereas both antagonists increased total cocaine intake. Overall, this procedure was sensitive to leftward, downward and rightward shifts in cocaine dose-effect functions and should be useful for evaluating the nature of pharmacological interactions between novel compounds and self-administered cocaine, as well as the potential for altering cocaine self-administration selectively with candidate treatments for cocaine abuse and dependence.