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 (0.1-0.32 mg/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 0.01 mg/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 0.032 mg/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.

Keywords: Amphetamine; Choice; Cocaine; Phendimetrazine; Phenmetrazine; Rhesus monkey.

Figure 1

Effects of continuous 14-day treatment with saline on choice between cocaine and food in rhesus monkeys (n=3). The top panels show saline treatment effects on cocaine dose-effect curves. Top and middle abscissae: unit dose of cocaine in milligrams per kilogram per injection (log scale). Top ordinates: percent cocaine choice. Middle ordinates: the number of choices completed per component. The bottom panels show summary data for total choices, food choices and cocaine choices summed across all cocaine doses. Bottom abscissae: experimental endpoint. Bottom ordinates: number of choices per session. All points and bars represent mean data ± SEM obtained during days 5-7 and 12-14 of each 14-day treatment period from three monkeys. Baseline points and bars represent mean data ± SEM obtained during the 3 days preceding each treatment period while saline was infused through the “treatment” lumen of the double lumen catheter.

Figure 2

Effects of continuous 14-day treatment with (+)-phendimetrazine (0.32 – 1.0 mg/kg/h) on choice between cocaine and food in rhesus monkeys (n=4). Filled symbols indicate significantly different (p < 0.05) from baseline (saline control) within a cocaine dose. Asterisk indicates significantly different (p < 0.05) from baseline (saline control) conditions. Numbers in parentheses indicate the number of subjects contributing to that data point if fewer than the total number of subjects (4) tested during treatment with 1.0 mg/kg/h phendimetrazine. This number indicates phendimetrazine treatment eliminated responding in one or more subjects during that component of the choice procedure. Other details as in Figure 1.

Figure 3

Effects of continuous 14-day treatment with (+)-phenmetrazine (0.1 – 0.32 mg/kg/h) on choice between cocaine and food in rhesus monkeys (n=5). Filled symbols indicate significantly different (p < 0.05) from baseline (saline control) within a cocaine dose. Other details as in Figure 1.

Figure 4

Effects of continuous 14-day treatment with d-amphetamine (0.032 – 0.1 mg/kg/h) on choice between cocaine and food in rhesus monkeys (n=6). Filled symbols indicate significantly different (p < 0.05) from baseline (saline control) within a cocaine dose. Asterisk indicates significantly different (p < 0.05) from baseline (saline control) conditions. Numbers in parentheses indicate the number of subjects contributing to that data point if fewer than the total number of subjects tested during treatment with 0.1 mg/kg/h d-amphetamine. This number indicates d-amphetamine treatment eliminated responding in one or more subjects during that component of the choice procedure. Other details as in Figure 1.