Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

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's efficacy in decreasing 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 = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure.

Results: In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32mg/kg, i.m.). 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 (0-0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32-3.2mg/kg/day, i.m.) or d-amphetamine (0.032-0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine.

Conclusions: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine's efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.

Keywords: Lisdexamfetamine effects in rhesus monkeys; addiction; choice; cocaine; lisdexamfetamine; rhesus monkey.

Figure 1.

Potency and time course of the discriminative stimulus effects of lisdexamfetamine (0.32–3.2mg/kg, i.m.) and d-amphetamine (0.032–0.32mg/kg, i.m.) in male rhesus monkeys (n = 4) trained to discriminate cocaine (0.32mg/kg, i.m.) versus saline. Abscissae: time in min or h after injection. Top ordinates: percent cocaine-appropriate responses. Bottom ordinates: rates of response in responses per second. Symbols above “S” and “C” represent the group averages for all saline- and cocaine-training sessions preceding test sessions, respectively. Filled symbols indicate statistical significance compared to saline at a given time point (p < 0.05).

Figure 2.

(A) Hysteresis plot of cocaine-appropriate responding in the discrimination procedure as a function of plasma d-amphetamine levels after 3.2mg/kg lisdexamfetamine administration. (B) For comparison, we also show a hysteresis plot of cocaine-appropriate responding and plasma (+)-phenmetrazine levels after 3.2mg/kg (+)-phendimetrazine administration from previously published results (Banks et al., 2013c).

Figure 3.

Effects of 7-day treatment with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.; A and C) and d-amphetamine (0.032–0.1mg/kg/h, i.v.; B and D) on cocaine versus food choice in rhesus monkeys (n = 3–4). The top panels show lisdexamfetamine and d-amphetamine effects on cocaine choice dose-effect curves. Abscissae: unit dose cocaine in mg/kg/injection. Ordinates: % cocaine choice. The bottom panels are summary results for lisdexamfetamine and d-amphetamine effects on the number of total choices, food choices, and cocaine choices summed across all cocaine doses. All points and bars represent mean data ± standard error of the mean obtained during days 5–7 of each 7-day treatment period from three monkeys (0.32 and 3.2mg/kg/day lisdexamfetamine) or four monkeys (1.0mg/kg/day lisdexamfetamine; all d-amphetamine doses). Filled symbols in the top panels and asterisks in the bottom panels indicate statistical significance compared to baseline conditions (saline; p < 0.05). Numbers in parentheses indicate the number of subjects contributing to that data point if less than the total number of subjects tested and indicative of a time point where a monkey failed to complete at least one ratio requirement during the choice component.

Figure 4

Effects of 7-day treatment with 0.1mg/kg/h d-amphetamine or 1.0mg/kg/day lisdexamfetamine treatment on the number of food (A) and cocaine (B) choices completed per choice session component in rhesus monkeys (n = 4). Abscissae: unit dose cocaine in mg/kg/injection that was available during each component of concurrent cocaine and food availability. Ordinates: choices completed per choice component. Filled symbols indicate statistical significant compared to baseline conditions (saline; p < 0.05).