• Journal Article

Preclinical assessment of lisdexamfetamine as a candidate 'agonist' medication for cocaine addiction: Effects in rhesus monkeys trained to discriminate cocaine or to self-administer cocaine in a cocaine-vs.-food choice procedure

Citation

Banks, M. L., Hutsell, B. A., Blough, B., Poklis, J. L., & Negus, S. S. (2015). Preclinical assessment of lisdexamfetamine as a candidate 'agonist' medication for cocaine addiction: Effects in rhesus monkeys trained to discriminate cocaine or to self-administer cocaine in a cocaine-vs.-food choice procedure. International Journal of Neuropsychopharmacology, 18(8), 1-10. DOI: 10.1093/ijnp/pyv009

Abstract

Background: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment efficacy to decrease cocaine consumption is unknown. Methods: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: 1) a cocaine discrimination procedure (training dose = 0.32 mg/kg cocaine, IM), and 2) a cocaine-vs.-food choice self-administration procedure. Results: In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2 mg/kg, IM) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32 mg/kg, IM). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0-0.1 mg/kg, IV) and food (1-g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for seven consecutive days with lisdexamfetamine (0.32-3.2 mg/kg/day, IM) or d-amphetamine (0.032-0.1 mg/kg/h, IV) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032 mg/kg/injection cocaine. Conclusions: Lisdexamfetamine has a slower onset and longer duration of action that amphetamine but retains amphetamine's efficacy to reduce cocaine-vs.-food choice in rhesus monkeys. These results support further consideration of lisdexamfetamine as a candidate 'agonist-based' medication for cocaine addiction