Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study.
OBJECTIVE
The pharmacologic profile of modafinil, an increasingly popular wake-promoting drug for narcolepsy treatment, differs from those of classic psychostimulants such as amphetamine. However, its brain targets are still a matter of debate. We hypothesized that modafinil could increase waking by inhibiting the sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such action could be direct or indirect via the potentiation of inhibition mediated by waking neurotransmitters. We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices. We further determined whether pretreatment with modafinil modifies the effect of noradrenaline, carbachol, serotonin, histamine, dopamine, or clonidine.


RESULTS
Pretreatment with modafinil specifically increased the inhibition of VLPO neurons induced by noradrenaline but had no effect when applied alone or in combination with other substances. Pretreatment with nisoxetine, a selective noradrenaline reuptake blocker, similarly increased the noradrenaline-induced inhibition of VLPO cells. Further, the potentiation by modafinil was minimized when modafinil and nisoxetine were applied together.


CONCLUSIONS
These results suggest that modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the VLPO. Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.
UMR 5167 CNRS, Physio-Pathologie des Réseaux Neuronaux du Cycle Veille-Sommeil, Institut Fédératif des Neurosciences de Lyon (IFNL, IFR19), Université Claude Bernard Lyon I, Lyon, France.
Thierry
T
Gallopin
Pierre-Hervé
PH
Luppi
Francis A
FA
Rambert
Armand
A
Frydman
Patrice
P
Fort
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002217:Carbachol / Q000378:metabolism; D018679:Cholinergic Agonists / Q000378:metabolism; D003000:Clonidine / Q000378:metabolism; D004594:Electrophysiology / Q000295:instrumentation; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D066298:In Vitro Techniques; D000077408:Modafinil; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010656:Phenylephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D012890:Sleep / Q000187:drug effects*; D013566:Sympathomimetics / Q000378:metabolism; D014795:Visual Pathways / Q000033:anatomy & histology* / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects*
D001559:Benzhydryl Compounds; D018679:Cholinergic Agonists; D018696:Neuroprotective Agents; D013566:Sympathomimetics; D005473:Fluoxetine; C011386:nisoxetine; D010656:Phenylephrine; D012701:Serotonin; D006632:Histamine; D002217:Carbachol; D003000:Clonidine; D000077408:Modafinil; D009638:Norepinephrine