Action of Modafinil—Increased Motivation Via the Dopamine Transporter Inhibition and D1 Receptors?

Published:February 05, 2010DOI:


      Modafinil is prescribed for the treatment of narcolepsy. It has been postulated that modafinil might treat cognitive disruption in neuropsychiatric disorders. The mechanisms underlying such modafinil-induced improvements in performance have yet to be delineated however. Recent evidence suggests that modafinil might block the dopamine transporter (DAT) and that the dopamine D1 receptor (D1R) might contribute to modafinil effects.


      Dopamine D1R wildtype (WT), heterozygous (HT), and knockout (KO) mice received vehicle, modafinil, or the selective DAT blocker GBR12909 in a progressive ratio breakpoint study.


      Both modafinil and GBR12909 increased motivation in the task as measured by an increase in breakpoint in WT and HT mice. These drug-induced increases in motivation were reduced in dopamine D1R HT mice relative to their WT littermates. The D1R KO mice did not respond in the task.


      These data support the hypothesis that modafinil increases motivation. Moreover, given the similarity of effects with GBR12909, the data corroborate evidence that the behavioral effects of modafinil might be due to DAT inhibition. Furthermore, the dopamine D1R might play a downstream role in mediating modafinil-induced increases in motivation. Thus, studies reporting cognition-enhancing effects of modafinil might have been influenced by its ability to increase motivation.

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        • Minzenberg M.J.
        • Carter C.S.
        Modafinil: A review of neurochemical actions and effects on cognition.
        Neuropsychopharmacology. 2008; 33: 1477-1502
        • Wu P.
        • Jones S.
        • Ryan C.J.
        • Michail D.
        • Robinson T.D.
        Modafinil-induced psychosis.
        Intern Med J. 2008; 38: 677-678
        • Mignot E.
        • Nishino S.
        • Guilleminault C.
        • Dement W.C.
        Modafinil binds to the dopamine uptake carrier site with low affinity.
        Sleep. 1994; 17: 436-437
        • Madras B.K.
        • Xie Z.
        • Lin Z.
        • Jassen A.
        • Panas H.
        • Lynch L.
        • et al.
        Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro.
        J Pharmacol Exp Ther. 2006; 319: 561-569
        • Volkow N.D.
        • Fowler J.S.
        • Logan J.
        • Alexoff D.
        • Zhu W.
        • Telang F.
        • et al.
        Effects of modafinil on dopamine and dopamine transporters in the male human brain: Clinical implications.
        JAMA. 2009; 301: 1148-1154
        • Wisor J.P.
        • Nishino S.
        • Sora I.
        • Uhl G.H.
        • Mignot E.
        • Edgar D.M.
        Dopaminergic role in stimulant-induced wakefulness.
        J Neurosci. 2001; 21: 1787-1794
        • Qu W.M.
        • Huang Z.L.
        • Xu X.H.
        • Matsumoto N.
        • Urade Y.
        Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil.
        J Neurosci. 2008; 28: 8462-8469
        • Zolkowska D.
        • Jain R.
        • Rothman R.B.
        • Partilla J.S.
        • Roth B.L.
        • Setola V.
        • et al.
        Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil.
        J Pharmacol Exp Ther. 2009; 329: 738-746
        • Turner D.C.
        • Clark L.
        • Pomarol-Clotet E.
        • McKenna P.
        • Robbins T.W.
        • Sahakian B.J.
        Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia.
        Neuropsychopharmacology. 2004; 29: 1363-1373
        • Faerden A.
        • Vaskinn A.
        • Finset A.
        • Agartz I.
        • Ann B.E.
        • Friis S.
        • et al.
        Apathy is associated with executive functioning in first episode psychosis.
        BMC Psychiatry. 2009; 9: 1
        • Bensadoun J.C.
        • Brooks S.P.
        • Dunnett S.B.
        Free operant and discrete trial performance of mice in the nine-hole box apparatus: Validation using amphetamine and scopolamine.
        Psychopharmacology. 2004; 174: 396-405
        • El-Ghundi M.
        • O'Dowd B.F.
        • Erclik M.
        • George S.R.
        Attenuation of sucrose reinforcement in dopamine D1 receptor deficient mice.
        Eur J Neurosci. 2003; 17: 851-862
        • Han D.D.
        • Gu H.H.
        Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs.
        BMC Pharmacol. 2006; 6: 6
        • Stoops W.W.
        • Lile J.A.
        • Fillmore M.T.
        • Glaser P.E.
        • Rush C.R.
        Reinforcing effects of modafinil: Influence of dose and behavioral demands following drug administration.
        Psychopharmacology. 2005; 182: 186-193
        • Wisor J.P.
        • Eriksson K.S.
        Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil.
        Neuroscience. 2005; 132: 1027-1034
        • Von Huben S.N.
        • Davis S.A.
        • Lay C.C.
        • Katner S.N.
        • Crean R.D.
        • Taffe M.A.
        Differential contributions of dopaminergic D1- and D2-like receptors to cognitive function in rhesus monkeys.
        Psychopharmacology. 2006; 188: 586-596
        • Cetin T.
        • Freudenberg F.
        • Fuchtemeier M.
        • Koch M.
        Dopamine in the orbitofrontal cortex regulates operant responding under a progressive ratio of reinforcement in rats.
        Neurosci Lett. 2004; 370: 114-117
        • Caine S.B.
        • Thomsen M.
        • Gabriel K.I.
        • Berkowitz J.S.
        • Gold L.H.
        • Koob G.F.
        • et al.
        Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice.
        J Neurosci. 2007; 27: 13140-13150
        • El-Ghundi M.
        • Fletcher P.J.
        • Drago J.
        • Sibley D.R.
        • O'Dowd B.F.
        • George S.R.
        Spatial learning deficit in dopamine D(1) receptor knockout mice.
        Eur J Pharmacol. 1999; 383: 95-106
        • Young J.W.
        • Goey A.
        • Minassian A.
        • Perry W.
        • Paulus M.P.
        • Geyer M.A.
        GBR 12909 administration as a mouse model of bipolar disorder mania: Mimicking quantitative assessment of manic behavior.
        Psychopharmacology (Berl). 2010; 208: 443-454