The behavioral and neurochemical effects of modafinil are mediated by the dopamine transporter

Abstract

Modafinil is a wake-promoting psychostimulant that is used for the treatment of sleep and mood disorders; however, its mechanism of action is unclear. Presently, modafinil neuropsychopharmacology was investigated using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64–128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) shifted the dose-response curves for cocaine and amphetamine to the left. Modafinil (100–300 μM) evoked [3H]overflow from rat striatal slices preloaded with [3H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. Nomifensine (10 μM) attenuated (~50%) modafinil-evoked [3H]overflow, and concentrations of modafinil (< 100 μM) that did not have intrinsic activity attenuated amphetamine (1–3 μM)-evoked [3H]overflow. Modafinil-evoked [3H]overflow was not altered by mecamylamine, and modafinil did not alter nicotine-evoked [3H]overflow, indicating that nicotinic acetylcholine receptors likely are not important for modafinil’s mechanism of action. These results indicate that modafinil is a psychostimulant that is similar to, but less potent than, amphetamine and cocaine. Modafinil’s behavioral effects likely are mediated through the dopamine transporter, but this mechanism is not solely responsible for modafinil’s efficacy. Supported by MU Research Board.