Evidence that modafinil blocks the brain dopamine transporter and decreases dopamine D2 receptor availability in humans

Abstract

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Objectives: Modafinil is a wake-promoting drug used to treat narcolepsy and under investigation for treating ADHD and stimulant addiction. Though there is evidence that the mechanisms of action of modafinil differ from those of stimulants like amphetamine and methylphenidate, which interact with dopamine transporters (DAT) elevating synaptic dopamine (DA) (Lin et al., 1996), a recent study reported significant blockade of DAT by modafinil (iv) in the baboon (Madras et al., 2006). Here we measured the effect of a therapeutic dose of modafinil on DAT and on extracellular DA in the human brain.

Methods: Five healthy males (age 32±5.2) were scanned twice with [11C]cocaine to measure DAT at baseline and 2 hours after modafinil (200 mg po) to assess DAT blockade. One week later, subjects were scanned with [11C]raclopride (D2 receptor radiotracer which is sensitive to changes in DA) before and after modafinil. We used the distribution volume ratio in striatum to that in cerebellum minus 1 (DVR-1) to estimate DAT and D2 receptor availability (Logan et al., 1990).

Results: Modafinil significantly blocked DAT in caudate (49.03±16.8%; p<0.005) and putamen (43.5±15.3%; p<0.004) and increased extracellular DA in striatum as evidenced by decreases in [11C]raclopride binding in caudate (5.3%± 3.23; p<0.02) and putamen (6.1%±2.7; p<0.006).

Conclusions: The levels of DAT blockade and DA increases after a therapeutic dose of modafinil are equivalent to those observed after therapeutic doses of methylphenidate, suggesting that DA enhancing mechanisms are relevant in the therapeutic effects of modafinil. Since drugs that increase DA have the potential for abuse these findings also raise concerns about the abuse liability of modafinil.

Research Support: DOE-OBER, NIDA and NIAAA