Journal of Pharmacology and Experimental Therapeutics 1999-10-01

Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine.

S B Caine, S S Negus, N K Mello, J Bergman

Index: J. Pharmacol. Exp. Ther. 291 , 353, (1999)

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Abstract

The reinforcing effects of D(1-like) and D(2-like) agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01-1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D(1-like) agonists SKF 82958 (0.001-0.032 mg i.v.) and SKF 77434 (0.001-0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D(2-like) agonists quinelorane (0.001-0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01-0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped dose-effect functions. Pretreatment with the D(1-like) agonists SKF 82958 and SKF 77434 (0.1-1.0 mg/kg i.p.) shifted the dose-effect function for cocaine self-administration downward, whereas pretreatment with the D(2-like) agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32-1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D(1-like) and D(2-like) agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D(1-like) agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D(2-like) agonists increased the intervals between self-administered cocaine injections. The results suggest that D(2-like) agonists, but not D(1-like) agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D(2) receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine.