Behavioral effects of cocaine: Interactions with D1 dopaminergic antagonists and agonists in mice and squirrel monkeys

The present study compared interactions among dopamine D1-like agonists and partial agonists with cocaine on the locomotor stimulant effects of cocain e, as well as the discriminative-stimulus effects of cocaine, and effects o f cocaine on rates of responding. Cocaine alone produced a dose-related sti mulation of locomotor activity in Swiss-Webster mice and a dose-related inc rease in the proportion of responses on the cocaine-appropriate response ke y in squirrel monkeys (Saimiri sciureus) trained to discriminate cocaine (0 .3 mg/kg i.m.) from saline. None of the D1 dopaminergic agents fully reprod uced these effects, with SKF 77434 producing marginal stimulation of locomo tor activity and SCH 23390, SCH 39166, and SKF 77434 producing some, althou gh incomplete substitution for cocaine in monkeys discriminating cocaine. T he D1 dopamine antagonists SCH 23390, SCH 39166, and A-69024 dose-dependent ly shifted the cocaine dose-effect curve for locomotor activity to the righ t and decreased the efficacy of cocaine. The same compounds shifted the dis criminative-stimulus effects of cocaine to the right without altering effic acy of cocaine. In contrast to the effects on locomotor activity, the maxim al shift to the right in the discriminative-stimulus effects of cocaine was similar to 3-fold, with higher doses of the antagonists producing no great er shifts in the cocaine dose-effect curve than with intermediate doses. Th e partial D1 agonists (+/-)-SKF 38393, (1) SKF 38393, and SKF 77434 also do se-dependently shifted the dose-effect curve for locomotor stimulant effect s to the right and decreased the maximal effect of cocaine. These compounds only shifted the discriminative-stimulus effects of cocaine to a 2-fold ma ximum. In general, cocaine effects on rates of responding in the subjects d iscriminating cocaine from saline were only minimally antagonized by coadmi nistration of the D1 dopaminergic agents. Both potency for producing behavi oral effects alone and in antagonizing the effects of cocaine were related to binding affinities assessed by displacement of [H-3] SCH 23390 from rat striatum. These results suggest that actions mediated by D1-like receptors contribute to the behavioral effects of cocaine. However, the various limit ations to the degree of antagonism accomplished indicate that D1-like dopam inergic actions appear to be more involved in the effects of cocaine on loc omotor activity, relatively less involved in the discriminative-stimulus ef fects of cocaine, and least involved in the effects of cocaine on operant r esponse rates. This differential involvement of D1 dopamine receptors in th ese various behavioral effects of cocaine suggests problems in predicting c linical efficacy of at least D1 receptor antagonists as potential treatment s for cocaine abuse. Additional studies are necessary to determine whether the antagonism of cocaine can predict therapeutic efficacy at all, and, if so, which effects when antagonized are the best predictors.