Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaineself-administration by humans

Rationale: Data obtained in laboratory animals and humans suggest that dopa mine DI receptor antagonists decrease cocaine self-administration and block cocaine's discriminative stimulus and subjective effects. Objectives: This study investigates the effects of the selective dopamine D1 antagonist, ec opipam (SCH 39166), on the reinforcing, cardiovascular, and subjective effe cts of cocaine in humans. Methods: Ten non-treatment-seeking cocaine smoker s (two females, eight males), residing on an inpatient research unit, were maintained on placebo and ecopipam (100 mg p.o.) in random order using a wi thin-subjects, cross-over design. Cocaine self-administration (0, 12, 25, a nd 50 mg) was tested beginning on the 5th day of each 8-day maintenance con dition. A six-trial choice procedure (cocaine vs $5 merchandise vouchers) w as utilized, with sessions consisting of one sample trial, when participant s smoked the cocaine dose available that day, and five choice trials, when participants chose between smoking the available cocaine dose or receiving one merchandise voucher. Results: In the presence of placebo cocaine, ecopi pam significantly decreased cocaine craving while increasing alcohol and to bacco craving. In the presence of active cocaine, ecopipam increased cocain e self-administration (12 mg) and increased ratings of "good drug effect," "high," "stimulated," and dose quality (25 and 50 mg). Ecopipam produced sm all but significant increases in blood pressure, regardless of cocaine dose . Conclusions: Maintenance on the long-acting dopamine D1 antagonist, ecopi pam, enhanced both cocaine self-administration as well as its subjective ef fects compared to maintenance on placebo. These data suggest that chronic a ntagonism of the dopamine D1 receptor may not be a useful approach for the treatment of cocaine abuse.