Modulation of cocaine's discriminative stimulus effects by dopamine D 1 agonists in rhesus monkeys

Abstract

Dopamine (DA) D 1 agonists are classified as high- or low-efficacy on the basis of in vitro functional measures as compared to DA. In monkeys self-administering cocaine, high-efficacy D 1 agonists have been shown to have reinforcing effects, while low-efficacy agonists do not. However, the relationship between D 1 agonist efficacy and cocaine-like discriminative stimulus effects, particularly in rhesus monkeys, is not clear. The present study investigated the discriminative stimulus effects of a high- (SKF 81297) and a low-efficacy (SKF 38393) D 1 agonist in rhesus monkeys ( n=4) trained to discriminate cocaine from saline using a two-lever drug discrimination procedure. In a second experiment, the effects of agonist pretreatments, as well as pretreatment with a D 1 antagonist, on cocaine's discriminative stimulus effects were evaluated. SKF 81297 (0.01–1.7 mg/kg) fully substituted for cocaine in three of four animals (>80% cocaine-appropriate responding), while SKF 38393 (0.3–10 mg/kg) occasioned <50% cocaine-appropriate responding in all subjects. When given as a pretreatment, neither agonist altered cocaine's discriminative stimulus effects at the doses tested. In contrast, the D 1 antagonist SCH 23390 attenuated cocaine's discriminative stimulus effects. These results indicate that D 1 agonists have cocaine-like discriminative stimulus effects in rhesus monkeys that are consistent with their in vitro efficacies. However, when given in combination with cocaine, D 1 agonist efficacy does not appear to be a major factor in modifying cocaine's discriminative stimulus effects.