Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys

• Phendimetrazine (PDM) is a pro-drug for the amphetamine-like monoamine releaser phenmetrazine (PM).
• Chronic oral PDM treatment decreased cocaine self-administration in rhesus monkeys for several weeks.
• Modest, transient effects on food self-administration were seen in some monkeys; tolerance developed to these effects.
• The relationships between oral PDM dose and blood PM levels varied across monkeys.
• Plasma PM concentrations were generally consistent with behavioral effects.

Chronic treatment with the monoamine releaser d-amphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine (PM), to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio (FR) schedule of reinforcement and self-administered cocaine (0.003–0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose–response curve, sessions were suspended and PDM was administered (1.0–9.0 mg/kg, p.o., b.i.d.). Cocaine self-administration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose–effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30–90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained responding in the third monkey and in the fourth subject, fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose–effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy.