COCAINE ANTAGONIST PROPERTIES OF D1 PARTIAL AGONIST SKF 83959: SQUIRREL MONKEYS

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Preclinical studies suggest that dopamine partial agonists warrant consideration as candidate medications for cocaine abuse. The benzazepine derivative SKF 83959 is a D1 partial agonist with a distinctive profile of agonist-like and antagonist properties. The present study assessed the potential antagonism of the behavioral effects of cocaine by SKF 83959. Squirrel monkeys were trained either to respond on a fixed-interval (FI) schedule of stimulus-shock termination or to discriminate cocaine from saline using a two-lever drug discrimination procedure. When combined with cocaine (0.03 - 10.0 mg/kg), SKF 83959 (0.10 - 1.0 mg/kg) attenuated both the rate-increasing effects of cocaine on fixed-interval responding and the discriminative stimulus (DS) effects of cocaine, resulting in dose-dependent rightward shifts in the dose-response functions. These effects are similar to those reported previously for the D1 antagonist SCH 39166, but not the D1 full agonist SKF 82958. In the absence of cocaine, SKF 83959 neither mimicked the DS effects of cocaine nor increased FI response rate. In observational studies, SKF 83959 (0.10 - 1.0 mg/kg) and SCH 39166 (0.01 - 0.30 mg/kg) produced dose-related decreases in locomotion, environmental manipulation, and self-directed behaviors (grooming, scratching) along with increases in the frequency of species-typical sleep postures. Although SCH 39166 included catalepsy and ataxia at the highest dose tested (0.30 mg/kg), these effects were not observed with SKF 83959 (1.0 mg/kg). These results suggest that SKF 83959 has properties of a functional cocaine antagonist with primarily sedative-like side effects.