| Co-Investigator(Kenkyū-buntansha) |
URADE Yoshihiro Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Head, 分子行動生物学部門, 研究部長 (10201360)
HAYAISHI Osamu Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Researcher, 分子行動生物学部門, 研究員 (40025507)
QU Wei-Min Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Researcher, 分子行動生物学部門, 研究員 (20332231)
江口 直美 (財)大阪バイオサイエンス研究所, 分子行動生物学部門, 研究副部長 (10250086)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Adenosine, a major humoral sleep-inducing substance, has 4 receptor subtypes expressed in the central nervous system, A_1, A_<2A>, A_<2B>, and A_3. Controversial evidence indicates that both A_1 receptor (A_1R) and A_<2A> receptor (A_<2A>R) subtype are involved in mediating the sleep-inducing effect of adenosine. Our examinations of sleep-wake cycles of wild-type (WT), A_1R-gene knockout (KO), and A_<2A>R-KO mice showed that A_1R-KO mice was identical to WT in non-rapid eye movement (non-REM) and REM sleep regulation under basal conditions, and exhibited the same amount of rebound sleep after 6-hr sleep deprivation during the light period ; A_<2A>R-KO mice showed a slight increase in non-REM and REM sleep during the dark period under basal conditions and exhibited almost no rebound of non-REM sleep after 6-hr sleep deprivation (manuscript in preparation). Caffeine at low doses inhibited non-REM and REM sleep in WT and A_1R-KO mice, but not at all in A_<2A>R-KO mice (Huang et al., Nat N
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eurosci,2005). We then pharmacologically identified the adenosine receptor subtype involved in sleep regulation. Cyclopentyl adenosine, an agonist of A_1R, did not change the sleep-wake cycle ; whereas CGS21680, an agonist of A_<2A>R, induced potent non-REM sleep, increased expression of fos protein in the ventrolateral preoptic area (VLPO), one of the sleep centers, and decreased fos expression in the histaminergic tuberomammillary nucleus (TMN), one of the arousal centers. GABAergic inhibition of TMN is involved in non-REM sleep induction by adenosine A_<2A>R-agonist (Hong, Huang et al., J Neurochem,2005). The selective activation of TMN induced wakefulness through H_1 receptor, and pharmacological blockade or genetic depletion of H_1 receptor decreased brief awakening during non-REM sleep episodes and stage transitions from sleep to wakefulness, increased sleep power density (Huang et al., PNAS,2006). These results, taken together, indicate that A_<2A>R, but not A_1R, is important for sleep-wake regulation, and that the neural network between VLPO and TMN regulates sleep and wakefulness, by means of a'flip-flop' mechanism. Less
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