| Project/Area Number |
18300129
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Osaka Bioscience Institute |
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Principal Investigator |
HAYASHI Osamu Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Researcher (40025507)
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| Co-Investigator(Kenkyū-buntansha) |
URADE Yoshihiro Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Head (10201360)
HUANG Zhi Li Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Vice head (10321704)
QU Wei Min Osaka Bioscience Institute, Department of Molecular Behavioral Biology, Researcher (20332231)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,360,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2007: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2006: ¥7,000,000 (Direct Cost: ¥7,000,000)
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| Keywords | leep-wake cycle / sleep substances / neural network / humoral regulation |
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| Research Abstract |
Administration of SeC14, a selective inhibitor of prostaglandin (PG) D synthase (PGDS), inhibited sleep dose-dependently in wild-type or hematopoietic PGDS knockout (KO) mice but not at all in lipocalin-type PGDS KO, hematopoietic and lipocalin-type PGDS double KO or PGD receptor (DP1R) KO mice. Furthermore, the DP1R antagonist reduced sleep of rats during infusion into the subarachnoid space under the rostral basal forebrain. These results clearly show that lipocalin-type PGDS/PGD2/DP1R system plays pivotal roles in the regulation of physiological sleep.
PGD_2 promotes sleep by activation of a sleep-center in the ventrolateral pre-optic area, and suppression of the wake-center in the histaminergic tuberomammillary nucleus (TMN). When we examined sleep-wake cycles of histamine H_1 receptors (H_1R) KO mice, H_1R KO mice showed sleep-wake cycles with fewer incidents of brief awakening, indicating that H_1R was involved in the regulation of behavioral state transitions from non-rapid eye movement (NREM) sleep to wakefulness.
Histaminergic TMN contains adenosine deaminase. Inhibition of adenosine deaminase or activation of adenosine A_1 receptor in the TMN increased NREM sleep and suppressed the histamine release in the brain. These results that indicate adenosine suppresses histaminergic activity and induces NREM sleep via A_1 receptors.
Histaminergic system had been implicated in the arousal effect of modafinil. However, we found that modafinil induced wakefulness in both H_1R KO and wild-type mice, indicating that histaminergic system was not essential for the modafinil-induced wakefulness. However, dopamine D_2 receptor KO mice exhibited attenuated modafinil-induced wakefulness. Moreover, pretreatment of D_2 receptor KO mice with Di receptor antagonist completely abolished arousal effects of modafinil. These findings indicate that the dopaminergic D_1 and D_2 receptor are essential for the wakefulness induced by modafinil.
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