Repeated administration of the D_1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine

Abstract.

Rationale: Dopaminergic compounds have been targeted as potential treatments for cocaine abuse because of the known role of dopamine systems in drug reinforcement. Recent preclinical and human data have focused on the D_1/5 antagonist, SCH 39166 (ecopipam), as a potential therapeutic agent. Objectives: The objective of the present study was to determine whether treatment with chronic ecopipam can blunt or block the subjective effects of cocaine in the absence of significant behavioral impairment or toxic physiological effects. Methods: Four doses of ecopipam (0, 10, 25, and 100 mg p.o.) were administered daily for 1 week each in double-blind, random order to inpatient 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 repeated dosing suggesting the development of tolerance. Ecopipam resulted in few direct subjective effects. Cocaine alone produced dose-dependent changes in prototypic subjective and physiological measures, however, ecopipam largely failed to alter either cocaine's direct effects or the desire for cocaine. Conclusions: Although the performance effects verify that these doses of ecopipam were behaviorally active, the absence of an attenuation of cocaine's effects or craving for cocaine in this chronic dosing paradigm suggests this compound is unlikely to be an effective pharmacotherapy for cocaine abuse.