Behavioral effects of cocaine: interactions with D1 dopaminergic antagonists and agonists in mice and squirrel...

The present study compared interactions among dopamine D1-like agonists and partial agonists with cocaine on the locomotor stimulant effects of cocaine, as well as the discriminative-stimulus effects of cocaine, and effects of cocaine on rates of responding. Cocaine alone produced a dose-related stimulation of locomotor activity in Swiss-Webster mice and a dose-related increase in the proportion of responses on the cocaine-appropriate response key in squirrel monkeys (Saimiri sciureus) trained to discriminate cocaine (0.3 mg/kg i.m.) from saline. None of the D1 dopaminergic agents fully reproduced these effects, with SKF 77434 producing marginal stimulation of locomotor activity and SCH 23390, SCH 39166, and SKF 77434 producing some, although incomplete substitution for cocaine in monkeys discriminating cocaine. The D1 dopamine antagonists SCH 23390, SCH 39166, and A-69024 dose-dependently shifted the cocaine dose-effect curve for locomotor activity to the right and decreased the efficacy of cocaine. The same compounds shifted the discriminative-stimulus effects of cocaine to the right without altering efficacy of cocaine. In contrast to the effects on locomotor activity, the maximal shift to the right in the discriminative-stimulus effects of cocaine was approximately 3-fold, with higher doses of the antagonists producing no greater shifts in the cocaine dose-effect curve than with intermediate doses. The partial D1 agonists (+/-)-SKF 38393, (+)-SKF 38393, and SKF 77434 also dose-dependently shifted the dose-effect curve for locomotor stimulant effects to the right and decreased the maximal effect of cocaine. These compounds only shifted the discriminative-stimulus effects of cocaine to a 2-fold maximum. In general, cocaine effects on rates of responding in the subjects discriminating cocaine from saline were only minimally antagonized by coadministration of the D1 dopaminergic agents. Both potency for producing behavioral effects alone and in antagonizing the effects of cocaine were related to binding affinities assessed by displacement of [(3)H]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 limitations to the degree of antagonism accomplished indicate that D1-like dopaminergic actions appear to be more involved in the effects of cocaine on locomotor activity, relatively less involved in the discriminative-stimulus effects of cocaine, and least involved in the effects of cocaine on operant response rates. This differential involvement of D1 dopamine receptors in these various behavioral effects of cocaine suggests problems in predicting clinical efficacy of at least D1 receptor antagonists as potential treatments 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.