Behavioral Evaluation of Modafinil and The Abuse-related Effects of Cocaine in Rhesus Monkeys

Abstract

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist-based medication to treat stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. Three studies were conducted to examine the behavioral effects of modafinil. In the first study, the discriminative stimulus effects of modafinil were evaluated in monkeys trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6/7 monkeys. In the second study, the effects of chronically administered modafinil (32-56 mg/kg/day, IV) on food- and cocaine-maintained operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate (0.003 mg/kg/inj) and peak (0.01 mg/kg/inj) reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic treatment with modafinil. In a third study, after extinction of cocaine self-administration, modafinil (32 and 56 mg/kg/day, IV) significantly increased saline self-administration on the first day of treatment. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. These data are generally consistent with clinical findings and provide new evidence that these preclinical models may be useful for predicting the effectiveness of novel medications for drug abuse treatment.