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Dopamine (DA) is critically involved in regulating processes responsible for the generation of complex movements and emotions, cognition, reward processing, and drug addiction.In contrast, the role assigned to DA in sleep-wake regulation has been relatively limited, because the activity of DA neurons in the ventral tegmental area and substantia nigra pars compacta is not significantly modulated by the sleep-wake cycle.The main DA receptors (R) in the brain are D1R and D2R.To clarify the roles of DA receptors in the sleep-wake regulation, we used D2R knockout (KO) mice and pharmacological manipulation.We found that the D2R blockade could reduce the sleep latency and increase amounts of non-rapid eye movement (NREM) sleep (Qiu, et al.Pharmacol Biochern Behav 2009).Modafinil is the most potent wake-promoting medicine for enhancing the extracellular DA level in the nucleus accumbens and the prefrontal cortex, and for increasing wakefulness in rats.By using D2R KO mice and D1R antagonist, we demonstrated that D1R and D2R are essential for the arousal effect of the wake promoting drug modafinil, with D2R being the receptor of primary importance (Qu et al.J Neurosci 2008).Compared with wild-type (WT) mice, D2R KO mice exhibited a significant decrease in wakefulness, with a concomitant increase in NREM and REM sleep and a drastic decrease in the low-frequency (0.75-2 Hz) electroencephalogram delta power of NREM sleep, especially during the first 4 h after lights off.When the KO mice were subjected to a cage change, the latency to sleep in the KO mice decreased to half of the level for WT mice.The D2R antagonist raclopride mimicked these effects in WT mice.When GBR12909, a DA transport inhibitor, was administered intraperitoneally, it induced wakefulness in WT mice in a dose-dependent manner, but its arousal effect was attenuated to one-third in the D2R KO mice (Qu et al.J Neurosci 2010).These results indicate that D2R plays an essential role in the maintenance of wakefulness.