Evaluation of the Reinforcing Effects of the Novel Dopamine Transport Inhibitor JJC8-091 in Monkeys

Abstract ID 87710 Poster Board 098 While there are no FDA-approved treatments for cocaine use disorder (CUD), one pharmacological strategy is to utilize DA transporter (DAT) inhibitors that could block the effects of cocaine but may not have abuse liability. The DAT inhibitor and releaser d-amphetamine has been shown to reduce cocaine self-administration (SA), although its misuse potential is considered a significant deterrent to FDA approval. Recently, several modafinil analogs have demonstrated promise in reducing cocaine SA in rats and monkeys. For example, JJC8-091 has been characterized as "atypical" and does not maintain SA in rats. Further, JJC8-091 mitigates many cocaine- and methamphetamine-induced behaviors that make it an appealing candidate for medication development. In contrast, JJC8-088 demonstrated a more typical DAT inhibitor behavior in rats. The purpose of the present set of studies was to evaluate the reinforcing effects of both compounds in monkeys. In Experiment 1, four cocaine-experienced male rhesus monkeys self-administered cocaine (0.001-0.3 mg/kg/injection) under a progressive-ratio (PR) schedule of reinforcement. Both JJC8-088 (0.001-0.3 mg/kg/injection) and JJC8-091 (0.1-3.0 mg/kg/injection) also functioned as reinforcers. JJC8-091 was less potent than either JJC8-088 or cocaine, which had similar potencies. Nevertheless, both JJC8-088 and JJC8-091 had equal reinforcing strength to cocaine, an unexpected finding. In Experiment 2, three drug-naïve cynomolgus monkeys (two females, one male) were trained to respond on a fixed-ratio schedule of food reinforcement. Saline and ascending doses of JJC8-091 were substituted for food. In all three monkeys, JJC8-091 functioned as a reinforcer. However, in Experiment 3, when the same three monkeys used in Experiment 2 were given access to cocaine and JJC8-091 under a concurrent drug-food choice paradigm, JJC8-091 was not chosen over food at previously reinforcing doses while cocaine was. These findings suggest that although JJC8-091 may be reinforcing in drug-experienced and drug-naive populations, its reinforcing effects can be mitigated by introducing access to an alternative reinforcer. Moreover, given that some reinforcing effects may be necessary to maintain compliance in a population with CUD, JJC8-091 may still be a viable candidate as a pharmacotherapy for cocaine misuse. This research was supported by the National Institute of Health grants from the National Institute on Drug Abuse P50 DA006634 (M.A.N.), R01 DA017763 (M.A.N.), F31 DA053776 (B.N.J.) and T32 DA041349-06 (M.I.A.).