Atypical neuroleptic profile of S 14506, a high affinity 5-HT 1A agonist with D-2 and 5-HT 1C antagonist activities

Abstract

Dopamine (DA) D1 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 D1 agonists have been shown to have reinforcing effects, while low-efficacy agonists do not. However, the relationship between D1 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) D1 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 D1 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 D1 antagonist SCH 23390 attenuated cocaine's discriminative stimulus effects. These results indicate that D1 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, D1 agonist efficacy does not appear to be a major factor in modifying cocaine's discriminative stimulus effects.