Comparison of interactions of D1-like agonists, SKF 81297, SKF 82958 and A-77636, with cocaine:: locomotor activity and drug discrimination studies in rodents

Rationale: Recent data suggest that dopamine (DA) D-1-like receptor full agonists may be potential pharmacotherapeutic agents for treating cocaine abuse. The structurally novel isochroman D-1-like agonist, A-77636, has not been well characterized and may prove to be useful as such an agent. Objectives: The interactions of cocaine and A-77636 were compared to those obtained with the better investigated benzazepine D-1-like dopamine agonists, SKF 82958 and SKF 81297. The alterations in the locomotor stimulant and discriminative-stimulus effects of cocaine by the full D-1-like dopamine receptor agonists were investigated across a full range of doses in order to characterize their interactions. Methods: Drug-naive Swiss-Webster mice were pretreated with SKF 81297, SKF 82958 or A-77636 (1-10 mg/kg) and cocaine (5-56 mg/kg) prior to a 30-min period in which locomotor activity was assessed. Rats were trained on a fixed ratio 20 (FR20) schedule to discriminate IP saline from cocaine (10 mg/kg) injections. Cocaine alone (1-10 mg/kg) and with either A-77636 (0.56-1.7 mg/kg), SKF 82958 (0.01-0.1 mg/kg) or SKF 81297 (0.1-0.56) were injected IP 5 min prior to a 15-min test session. Results: Cocaine maximally stimulated activity at 20-40 mg/kg with higher and lower doses stimulating activity less. Each D-1-like agonist produced a dose-related decrease in cocaine-induced locomotor activity and lowered its maximal rate. Each of the D-1-like agonists partially substituted for cocaine, with maximal substitution approximating 49, 35, and 24% for SKF 81297, SKF 82958, and A-77636, respectively. SKF 82958 significantly shifted the cocaine dose-effect curve approximately 3-fold to the left. With SKF 81297, there was a trend towards a leftward shift of cocaine dose effects, however the change was not statistically significant. In contrast to the other two D-1-like agonists, A-77636 either did not affect the cocaine dose-effect curve or shifted it to the right. Conclusions: All three agonists produced similar effects on cocaine-induced locomotor activity, however the discriminative-stimulus effects of cocaine were affected differently by the D-1 agonists. These results suggest fundamental differences in the actions of these D-1 agonists. Because A-77636 consistently attenuated the present effects of cocaine, it may prove more useful than the others as a pharmacotherapy to treat cocaine abuse.