Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation.
Although the wake-promoting drug modafinil has been shown to bind quite exclusively to the dopamine transporter (DAT), its action in the brain has been thought to be partially independent from the facilitation of the dopaminergic signals. Here we used electrophysiological and amperometric techniques to investigate the effects of modafinil on the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and on the synaptic overflow of dopamine in the dorsal striatum from the sliced tissue of wild-type and cocaine-insensitive genetically modified mice (DAT-CI). Moreover, we examined the consequences of modafinil administration on the locomotor behavior of wild-type and DAT-CI mice. In in vitro experiments, modafinil inhibited the spontaneous firing discharge of the dopaminergic neurons. More consistently, it potentiated firing inhibition and the membrane responses caused by exogenously applied dopamine on these cells. Furthermore, it augmented the stimulus-evoked outflow of DA in the striatum. Noteworthy, modafinil caused locomotor activation in wild-type mice. On the other hand, neither the electrophysiological nor the behavioral effects of modafinil were detected in DAT-CI animals. These results demonstrate that modafinil potentiates brain dopaminergic signals via DAT inhibition by acting at the same binding site of cocaine. Therefore, this mechanism of action explains most of the pharmacological properties of this compound in the clinical setting.
IRCSS Fondazione Santa Lucia, 00143 Rome, Italy.
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Federici
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Latagliata
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Rizzo
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Ledonne
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Gu
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Romigi
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Nisticò
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Puglisi-Allegra
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Mercuri
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D059290:Dopaminergic Neurons / Q000187:drug effects*; D051379:Mice; D008817:Mice, Mutant Strains; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D064690:Wakefulness-Promoting Agents / Q000494:pharmacology*
D001559:Benzhydryl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D064690:Wakefulness-Promoting Agents; D003042:Cocaine; D000077408:Modafinil; D004298:Dopamine
CPA; DAT; SNpc; aCSF; amperometry; artificial cerebrospinal fluid; constant potential amperometry; dopamine overflow; dopamine transporter; i.p.; intraperitoneally; locomotor activation; modafinil; substantia nigra pars compacta