Dopaminergic D1 and D2 receptors are essential
for the arousal effect of modafinil

by
Qu WM, Huang ZL, Xu XH, Matsumoto N, Urade Y.
Department of Molecular Behavioral Biology,
Osaka Bioscience Institute,
Suita, Osaka 565-0874, Japan.
J Neurosci. 2008 Aug 20;28(34):8462-9.


ABSTRACT

Modafinil is a wake-promoting compound with low abuse potential used in the treatment of narcolepsy. Although the compound is reported to affect multiple neurotransmitter systems such as catecholamines, serotonin, glutamate, GABA, orexin, and histamine, however, the molecular mechanism by which modafinil increases wakefulness is debated. Herein we used dopamine (DA) D(2) receptor (D(2)R)-deficient mice combined with D(1)R- and D(2)R-specific antagonists to clarify the role of DA receptors in the arousal effects of modafinil. In wild-type mice, intraperitoneal modafinil induced wakefulness in a dose-dependent manner. Pretreatment with either D(1)R antagonist SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] at 30 microg/kg or D(2)R antagonist raclopride at 2 mg/kg blocked the arousal effects of low-dose modafinil at 22.5 and 45 mg/kg. When modafinil was given at 90 and 180 mg/kg, pretreatment of D(1)R antagonist did not affect the wakefulness at all, whereas D(2)R antagonist significantly attenuated the wakefulness to the half level compared with vehicle control. Similarly, D(2)R knock-out (KO) mice exhibited attenuated modafinil-induced wakefulness. However, pretreatment of D(2)R KO mice with D(1)R antagonist completely abolished arousal effects of modafinil. These findings strongly indicate that dopaminergic D(1)R and D(2)R are essential for the wakefulness induced by modafinil.


Mood
Orexins
Serotonin
Dopamine
Glutamate
The sleep-switch
Modafinil: structure
Atypical depression
Modafinil and the aviator
Modafinil: pharmacokinetics
Modafinil and the marmoset
Modafinil wakes up sleepy flies
Modafinil versus amphetamine
Modafinil versus methylphenidate
Modafinil v amphetamine v placebo
Fatigue, sleepiness in major depression
Modafinil plus SSRIs for depression and fatigue
Dosing regimen effects of modafinil in narcolepsy
Mood-lifting effect of caloric restriction is mediated by orexin
Modafinil plus selective serotonin reuptake inhibitors (SSRIs)
Modafinil: a dual noradrenergic-dopaminergic mechanism of action?



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