Stimulant abuse is a persistent public health problem with no FDA-approved pharmacotherapy.Although monoamine-releasing drugs such as d-amphetamine can decrease cocaine selfadministration in human and animal laboratory studies, their potential for abuse limits clinical utility. "Abuse-deterrent" formulations of monoamine releasers such as pro-drugs hold greater clinical promise if their abuse potential is, as theorized, lower than that of cocaine. In these studies, we determined the reinforcing strength of phendimetrazine (PDM), a pro-drug for the amphetamine-like monoamine releaser phenmetrazine; both drugs have been shown to decrease cocaine self-administration in laboratory animals. To date, no study has directly compared PDM (Schedule III) with cocaine (Schedule II) under progressive-ratio (PR) schedules of reinforcement, which are better suited to directly compare reinforcing strength of drugs compared to fixed-ratio schedules. Dose-response curves for cocaine (0.001-0.3 mg/kg per injection) and PDM (0.1-1.0 mg/kg per injection) were generated in six cocaine-experienced male rhesus monkeys during 4-hr sessions with a 20-min limited-hold (LH20). Under these conditions, the maximum number of injections was not significantly different between cocaine and PDM. The reinforcing strength of doses situated on the peaks of the cocaine and PDM dose-effect curves were re-determined with a LH60. The mean number of injections increased for both drugs, but not for saline. Cocaine presentations resulted in significantly higher peak injections than PDM at LH60, which is consistent with the lower scheduling of PDM. These results support PDM as Schedule III and highlight the importance of schedule parameters when comparing reinforcing strength of drugs using a PR schedule.Significance Statement. One strategy for reducing cocaine use is to identify a treatment that substitutes for cocaine, but has lower abuse potential. In a rhesus monkey model of drug abuse, this study compared the reinforcing strength of cocaine and phendimetrazine, a drug that has been shown to decrease cocaine use in some studies.

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Cocaine use disorder (CUD) continues to be a major public health and social problem with >1.5 million users resulting in 14,556 deaths in 2017 in the United States and with no FDA‐approved medications available (Volkow and Koob, 2016). Preclinical studies in nonhuman primates have shown that monoamine releasers such as amphetamine can reduce the reinforcing strength of cocaine under several schedules of cocaine self‐administration (SA; Czoty et al. 2010; Negus et al. 2003a, b). However, the high abuse potential of this category of drugs has hindered advancement of their clinical use for treatment of CUD. More recently, preclinical researchers have investigated phendimetrazine (PDM), an FDA‐approved Schedule III anorectic agent, with evidence of efficacy in animal models (Banks and Negus, 2013; Czoty et al. 2016). As a pro‐drug for the monoamine releaser phenmetrazine, PDM has a slow onset and long duration of action. Only two studies (Griffiths et al. 1976; Corwin et al. 1987) have evaluated the reinforcing effects of PDM, with opposite conclusions. The goal of the present study was to compare, in the same subjects, the efficacy of PDM to decrease cocaine SA and the reinforcing strength of PDM relative to cocaine. For 5 consecutive days, three adult male rhesus monkeys responded under a daily fixed‐ratio 20 schedule of food presentation, which, on the fifth day, was followed by a progressive‐ratio (PR) schedule of cocaine (0.003–0.3 mg/kg/injection) presentation (limited hold 30‐min, maximum 4‐hr). PDM was administered daily (1.0–6.0 mg/kg, PO, BID). The primary dependent variable under the PR schedule was the number of injections delivered. Under baseline conditions, monkeys typically earned 10 food reinforcers and the number of cocaine injections was characterized as an inverted U‐shaped function of dose. Under treatment conditions, in two subjects, food‐maintained responding was disrupted at higher PDM doses that also decreased cocaine SA. In the third subject, food reinforcement was not affected and PDM did not show efficacy in decreasing cocaine SA. When PDM (0.1–1.0 mg/kg/injection) was substituted for cocaine, it functioned as a reinforcer in all three subjects; the number of injections observed at peak doses of PDM (0.3 and 1.0 mg/kg/injection) were similar to those observed at the peak dose of cocaine (0.03 mg/kg/injection). These findings suggest that PDM has abuse liability and was ineffective in decreasing cocaine SA. These data do not support the use of PDM as a potential treatment for CUD.Support or Funding InformationP50 DA06634‐27This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.