Evaluation of the Reinforcing Strength of Phendimetrazine Using a Progressive-Ratio Schedule of Reinforcement in Rhesus Monkeys

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 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.

Behavioral and neuronal extracellular vesicle biomarkers associated with nicotine's enhancement of the reinforcing strength of cocaine in female and male monkeys

“…With the PR schedule of reinforcement, it appears that a ceiling effect may have been evident in some monkeys, such that the break point only occurred because the 4 hour session timed out. However, based on recent findings in which PR parameters were manipulated using a within-subjects design [ 61 ], it is likely that a longer session length, without changing other parameters, would have increased the break point for both cocaine and cocaine + nicotine and not changed the overall conclusion for this experiment. As it relates to the cocaine vs. food choice studies, we could expand this paradigm to include studies involving reinstatement/relapse, as described by others [ 73 ].…”

“…Drug self-administration sessions began at approximately 8:00 AM each day and were conducted 5–7 days per week. Detailed methods have been described previously [ 61 ]. Briefly, daily behavioral sessions were comprised of a multiple schedule, in which the first component was a fixed-ratio (FR) 20 schedule of food availability, in which 20 responses on the right switch were required to deliver a food pellet.…”