Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys

Abstract

Background
The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4).

Methods
Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0–0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose–effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32–1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1–0.32mg/kg/h; N=5) and d-amphetamine (0.032–0.1mg/kg/h; N=6) were also examined for comparison.

Results
During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects.

Conclusions
These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability.