Repeated administration of the D-1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine

Rationale: Dopaminergic compounds have been targeted as potential treatment s for cocaine abuse because of the known role of dopamine systems in drug r einforcement. Recent preclinical and human data have focused on the D-1/5 a ntagonist, SCH 39166 (ecopipam), as a potential therapeutic agent. Objectiv es: The objective of the present study was to determine whether treatment w ith chronic ecopipam can blunt or block the subjective effects of cocaine i n the absence of significant behavioral impairment or toxic physiological e ffects. Methods: Four doses of ecopipam (0, 10, 25, and 100 mg p.o.) were a dministered daily for 1 week each in double-blind, random order to inpatien t cocaine-dependent volunteers (n=10). Cocaine challenge doses (0, 25, and 50 mg/70 kg i.v.) were administered on the 7th day in ascending order, 1 h apart. Results. Ecopipam alone produced reliable dose-dependent deficits in performance on the digit symbol substitution task (DSST) and the circular lights task, but not a balance task. Impairment on the DSST waned with repe ated dosing suggesting the development of tolerance. Ecopipam resulted in f ew direct subjective effects. Cocaine alone produced dose-dependent changes in prototypic subjective and physiological measures, however, ecopipam lar gely failed to alter either cocaine's direct effects or the desire for coca ine. Conclusions: Although the performance effects verify that these doses of ecopipam were behaviorally active, the absence of an attenuation of coca ine's effects or craving for cocaine in this chronic dosing paradigm sugges ts this compound is unlikely to be an effective pharmacotherapy for cocaine abuse.