Effects of environmental manipulations and treatment with bupropion and risperidone on choice between methamphetamine and food in Rhesus monkeys

Abstract

Preclinical and human laboratory choice procedures have been invaluable in improving our knowledge of the neurobiological mechanisms of drug reinforcement and in the drug development process for candidate medications to treat drug addiction. However, little is known about the neuropharmacological mechanisms of methamphetamine vs food choice. The aims of this study were to develop a methamphetamine vs food choice procedure and determine treatment effects with two clinically relevant compounds: the monoamine uptake inhibitor bupropion and the dopamine antagonist risperidone. Rhesus monkeys (n=6) responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, FR10 schedule) during 7-day bupropion (0.32-1.8 mg/kg/h) and risperidone (0.001-0.0056 mg/kg/h) treatment periods. For comparison, effects of removing food pellets or methamphetamine injections and FR response requirement manipulations were also examined. Under saline treatment conditions, food was preferred over no methamphetamine or small unit methamphetamine doses (0.01-0.032 mg/kg/injection). Larger methamphetamine doses resulted in greater methamphetamine preference and 0.32 mg/kg/injection methamphetamine maintained near exclusive preference. Removing food availability increased methamphetamine choice, whereas removing methamphetamine availability decreased methamphetamine choice. Methamphetamine choice was not significantly altered when the FR response requirements for food and drug were the same (FR100:FR100 or FR10:FR10). Risperidone treatment increased methamphetamine choice, whereas bupropion treatment did not alter methamphetamine choice up to doses that decreased rates of operant behavior. Overall, these negative results with bupropion and risperidone are concordant with previous human laboratory and clinical trials and support the potential validity of this preclinical methamphetamine vs food choice model.