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.

Federici, M., Latagliata, E., Rizzo, F., Ledonne, A., Gu, H., Romigi, A., et al. (2013). Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation. NEUROSCIENCE, 252, 118-124 [10.1016/j.neuroscience.2013.07.071].

Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation

FEDERICI, MASSIMO;LEDONNE, ADA;NISTICO', ROBERT GIOVANNI;MERCURI, NICOLA BIAGIO
2013-11-12

Abstract

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.
12-nov-2013
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
Animals; SNpc; dopamine overflow; Benzhydryl Compounds; aCSF; dopamine transporter; Wakefulness-Promoting Agents; Dopamine; locomotor activation; constant potential amperometry; Cocaine; amperometry; DAT; substantia nigra pars compacta; Brain; Mice; i.p.; Dopaminergic Neurons; intraperitoneally; Mice, Mutant Strains; Patch-Clamp Techniques; Dopamine Plasma Membrane Transport Proteins; artificial cerebrospinal fluid; modafinil; Motor Activity; CPA
Federici, M., Latagliata, E., Rizzo, F., Ledonne, A., Gu, H., Romigi, A., et al. (2013). Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation. NEUROSCIENCE, 252, 118-124 [10.1016/j.neuroscience.2013.07.071].
Federici, M; Latagliata, E; Rizzo, F; Ledonne, A; Gu, H; Romigi, A; Nistico', Rg; Puglisi Allegra, S; Mercuri, Nb
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
Nsci'13Moda.pdf

solo utenti autorizzati

Descrizione: Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation. Neuroscience
Licenza: Copyright dell'editore
Dimensione 817.37 kB
Formato Adobe PDF
817.37 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/101301
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 17
social impact