Abstract
Stimulant abuse is a persistent public health problem with no FDA-approved pharmacotherapy. Although monoamine-releasing drugs such as d-amphetamine can decrease cocaine self-administration 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.
- The American Society for Pharmacology and Experimental Therapeutics