Effects of modafinil: studies on cocaine self‐administration, neurochemistry, and activity in rhesus macaques.

Abstract

Modafinil is currently used as a treatment for excessive daytime sleepiness. Increasing evidence suggests modafinil affects the dopamine transporter. Therefore, we examined the effects of modafinil (10 mg/kg; i.v.) on daytime locomotor activity, cocaine self‐administration, reinstatement of cocaine‐maintained behavior, and extracellular dopamine levels. Locomotor activity was measured in the home cage using Actiwatch telemetry, with four days of baseline recording preceding a morning injection. Administration of modafinil did not significantly increase daytime locomotor activity. Monkeys self‐administered cocaine under a second order, fixed ratio 20 schedule; pretreatment with modafinil did not have a significant effect on cocaine self‐administration. Cocaine maintained responding was then extinguished and extinction level responding maintained for a minimum of two days before priming with modafinil. Modafinil was able to significantly reinstate extinguished cocaine‐maintained behavior. Finally, dopamine levels following modafinil administration were measured using in vivo microdialysis followed by sample analysis using high performance liquid chromatography. Modafinil significantly increased dopamine overflow within the caudate nucleus approximately 20 minutes after injection. PET imaging will determine DAT occupancy associated with behavioral and neurochemical effects. Modafinil did not appear to have behavioral stimulant effects at 10 mg/kg, but at this dose does appear to have dopaminergic effects as measured by in vivo neurochemistry and cocaine reinstatement assays.