Previous studies suggest that D1 receptor partial agonists may be viable candidates for development as
pharmacotherapies for
cocaine addiction. This study investigated the ability of the D1 receptor partial agonists SKF 83959 and
SKF 77434 to modulate the behavioral effects of
cocaine and compared these effects with those of the reference D1 receptor antagonist
SCH 39166 and D1 receptor agonists
SKF 81297 and
6-Br-APB. Squirrel monkeys were trained either to respond under a fixed-interval schedule of stimulus-
shock termination or to discriminate
cocaine from vehicle (procedures useful for evaluating the behavioral stimulant and subjective effects of
cocaine, respectively). Additional monkeys were studied with quantitative observational techniques to evaluate the effects of the drugs on various forms of motor behavior. Like
SCH 39166, but unlike
SKF 81297 and
6-Br-APB, the D1 receptor partial agonists attenuated the behavioral stimulant and discriminative stimulus effects of
cocaine in a dose-dependent manner, although maximum antagonism produced by
SKF 77434 was not always as great as that produced by SKF 83959 or
SCH 39166. In observational studies, SKF 83959 and
SKF 77434 produced less severe disruptions in motor behavior than did
SCH 39166 and, for SKF 83959, showed a greater separation between the dose required to antagonize the behavioral effects of
cocaine and the dose that induced
catalepsy (>/=33-fold). These results suggest that D1 receptor partial agonists can act as functional
cocaine antagonists with less severe behavioral effects than D1 receptor antagonists. The prominent
cocaine-antagonist properties and the low incidence of motoric side effects of SKF 83959 may reflect its unique binding profile at D1 as well as nondopaminergic receptors.