Abstract

While there are no FDA-approved treatments for cocaine use disorder (CUD), several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine-food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, i.v. pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys (n=3/drug). In behavioral studies, acute and chronic administration of both compounds were evaluated in these same monkeys responding under a concurrent food vs. cocaine (0, 0.003-0.1 mg/kg/injection) schedule of reinforcement. In nonhuman primate striatum, JJC8-088 had higher DAT affinity compared to JJC8-091 (14.4 {plus minus} 9 vs. 2,730 {plus minus} 1,270 nM, respectively). Both JJC compounds had favorable plasma pharmacokinetics for behavioral assessments, with half-lives (t_1/2) of 1.1 h and 3.5 h for JJC8-088 (0.7 mg/kg, i.v.) and JJC8-091 (1.9 mg/kg, i.v.), respectively. Acute treatment with both compounds shifted the cocaine dose-response curve to the left. Chronic treatment with JJC8-088 decreased cocaine choice in two of the three monkeys, while JJC8-091 only modestly reduced cocaine allocation in one monkey. Differences in affinities of JJC8-091 DAT binding in monkeys compared to rat, may account for the poor rodent-to-monkey translation. Future studies should evaluate atypical DAT blockers in combination with behavioral interventions that may further decrease cocaine choice.

Significance Statement Cocaine use disorder (CUD) remains a significant public health problem with no FDA-approved treatments. The ability of drugs that act in the brain in a similar manner to cocaine, but with lower abuse liability, has clinical implications for a treatment of CUD.