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The Journal of Neuroscience, August 20, 2008, 28(34):8462-8469; doi:10.1523/JNEUROSCI.1819-08.2008

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Behavioral/Systems/Cognitive
Dopaminergic D₁ and D₂ Receptors Are Essential for the Arousal Effect of Modafinil

Wei-Min Qu,¹ Zhi-Li Huang,^1,2,3 Xin-Hong Xu,^1,2,3 Naomi Matsumoto,¹ and Yoshihiro Urade¹

¹Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan, ²State Key Laboratory of Medical Neurobiology, and ³Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai 200032, China

Correspondence should be addressed to either of the following: Yoshihiro Urade, Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan, Email: uradey{at}obi.or.jp; or Zhi-Li Huang, State Key Laboratory of Medical Neurobiology and Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai 200032, China, Email: huangzljp{at}yahoo.com.cn

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) D₂ receptor (D₂R)-deficient mice combined with D₁R- and D₂R-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 D₁R antagonist SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] at 30 µg/kg or D₂R 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 D₁R antagonist did not affect the wakefulness at all, whereas D₂R antagonist significantly attenuated the wakefulness to the half level compared with vehicle control. Similarly, D₂R knock-out (KO) mice exhibited attenuated modafinil-induced wakefulness. However, pretreatment of D₂R KO mice with D₁R antagonist completely abolished arousal effects of modafinil. These findings strongly indicate that dopaminergic D₁R and D₂R are essential for the wakefulness induced by modafinil.

Key words: dopamine receptor; EEG; knock-out mice; modafinil; sleep; wakefulness

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Received April 25, 2008; revised June 20, 2008; accepted July 19, 2008.

Correspondence should be addressed to either of the following: Yoshihiro Urade, Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan, Email: uradey{at}obi.or.jp; or Zhi-Li Huang, State Key Laboratory of Medical Neurobiology and Department of Pharmacology, Shanghai Medical College of Fudan University, Shanghai 200032, China, Email: huangzljp{at}yahoo.com.cn

Related articles in J. Neurosci.:

Dopamine D₁ and D₂ Receptor Family Contributions to Modafinil-Induced Wakefulness

Jared W. Young
J. Neurosci. 2009 29: 2663-2665. [Full Text]  

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