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 (0–0.1 mg/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 (0.32–1.0 mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1–0.32 mg/kg/h; N = 5) and d-amphetamine (0.032–0.1 mg/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 0.1 mg/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.

Introduction

The goal of an agonist-based pharmacotherapy for the treatment of cocaine dependence is to utilize a medication that has pharmacological effects similar to the abuse drug, a slow onset to reduce abuse liability, and a long duration of action to facilitate medication compliance (Grabowski et al., 2004). For over a decade, the dopamine/norepinephrine vs. serotonin-selective monoamine releaser d-amphetamine has consistently demonstrated efficacy to decrease cocaine self-administration across a broad range of experimental conditions and in a range of species, including rats (Chiodo et al., 2008, Thomsen et al., 2013), nonhuman primates (Czoty et al., 2011, Negus, 2003), and humans (Greenwald et al., 2010, Rush et al., 2010). Moreover, the efficacy of d-amphetamine to decrease cocaine self-administration in these preclinical and human laboratory studies has been consistent with results from clinical trials (Grabowski et al., 2001, Mariani et al., 2012, Schmitz et al., 2012). Despite this extant evidence for efficacy of d-amphetamine as a candidate agonist medication for cocaine dependence, the clinical utility of d-amphetamine is hindered by its own abuse liability and associated schedule II controlled substance status. The acceptability of agonist-based medications might benefit from identification of novel compounds that have lower abuse liability than amphetamine, but that retain amphetamine's efficacy to decrease cocaine self-administration and its long duration of action.

One approach to decrease the abuse liability of a candidate medication is the development of a prodrug to slow onset of drug effects (Balster and Schuster, 1973, Huttunen et al., 2011, Schindler et al., 2009). Phenmetrazine is a dopamine/norepinephrine vs. serotonin-selective monoamine releaser that has cocaine-like discriminative stimulus effects (Banks et al., 2013a, Negus et al., 2009) and decreases cocaine self-administration in nonhuman primates (Banks et al., 2011b, Banks et al., 2013b, Negus et al., 2009). However, like d-amphetamine, phenmetrazine has a high abuse liability and is no longer clinically available in the United States (Corwin et al., 1987, Griffiths et al., 1979). Phendimetrazine is an N-methyl analog of phenmetrazine that functions as a prodrug for phenmetrazine (Banks et al., 2013a, Rothman et al., 2002). Furthermore, phendimetrazine appears to have reduced abuse potential compared to phenmetrazine in certain drug self-administration assays (Corwin et al., 1987), and is available as a schedule III anorectic approved for the short term treatment of obesity. Overall, this body of literature supports further research on phendimetrazine as a candidate pharmacotherapy for cocaine dependence (Banks et al., 2013a, Rothman et al., 2002, Stoops and Rush, 2013).

The aim of the present study was to determine the effects of 14-day continuous treatment with phendimetrazine on cocaine self-administration by rhesus monkeys responding under a concurrent cocaine vs. food choice procedure that has been used previously to examine effects of other candidate medications (Banks et al., 2011b, Banks et al., 2013b, Negus, 2003). Effects of 14-day treatment with phenmetrazine and d-amphetamine on cocaine choice were also examined for comparison. We hypothesized that all three compounds would produce similar decreases in cocaine choice and reciprocal increases in food choice. These expected results would support further consideration and development of phendimetrazine as a candidate pharmacotherapy for cocaine dependence.