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Molecular mechanism of wakefulness regulation

觉醒调节的分子机制

基本信息

批准号：
16300123
负责人：
HAYAISHI Osamu
金额：
$ 9.6万
依托单位：
Osaka Bioscience Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300123/
关键词：
Wakefulness Brief awakening Gene knockout mice Histamine TMN GABA A_<2A> receptor Caffeine Wakefulness Brief awakeming Gene knockout mice Histamine TMN GABA A2A receptor

项目摘要

Under baseline conditions, gene knockout (KO) mice for histamine H_1 receptors (H_1R) showed sleep-wake cycles essentially identical to those of wild-type (WT) mice but with fewer incidents of brief awakening (<16-sec epoch) during non-rapid eye movement (NREM) sleep and a shorter latency for initiating NREM sleep after an i.p. injection of saline. The H_1R antagonist, pyrilamine, mimicked these effects in WT mice. A histamine H_3 receptor antagonist, ciproxifan, increased wakefulness in WT mice after an i.p. injection in a dose-dependent manner but not at all in H_1R KO mice, although the histamine release from the frontal cortex was increased in both genotypes of mice. These results indicate that H_1R is involved in the regulation of state transitions from NREM sleep to wakefulness and that the arousal effect of the H_3 antagonist completely depends on the activation of histaminergic system through H_1R.Administration of an adenosine A_<2A> receptor (A_<2A>R) agonist, CGS21680, to th … More e rat basal forebrain inhibited both wakefulness and the histamine release in the frontal cortex. Microdialysis studies with anesthetized rats revealed that the A_<2A>R-agonist administration inhibited the histamine release in the cortex and increased the GABA release in the histaminergic tuberomammillary nucleus (TMN) but not in the cortex. The A_<2A>R-agonist-induced inhibition of the histamine release was reversed by the administration of GABA antagonist, picrotoxin, into the TMN, indicating that the GABAergic inhibition of TMN was involved in the inhibition of wakefulness by A_<2A>R agonist. Caffeine is the most popular substance to induce wakefulness but the receptor subtype involved in the caffeine-induced wakefulness remained unclear. When we administrated caffeine in WT, adenosine A_1 receptor (A_1R)-KO, and A_<2A>R-KO mice, caffeine induced wakefulness in WT and A_1R-KO mice but not at all in A_<2A>R-KO mice, indicating that the arousal effect of caffeine completely depends on A_<2A>R, but not A_1R. Less

在基线条件下，组胺H_1受体(H_1R)基因敲除(KO)小鼠表现出与野生型(WT)小鼠基本相同的睡眠-觉醒周期，但在非快速眼动(NREM)睡眠中短暂觉醒(16秒周期)的事件更少，并且在ip后启动NREM睡眠的潜伏期更短。注射生理盐水。H_1R拮抗剂吡咯胺在WT小鼠身上也有类似的作用。组胺H_3受体拮抗剂环丙昔芬可增加WT小鼠ip后的觉醒。H_1R-KO小鼠注射组胺呈剂量依赖关系，但在H_1R-KO小鼠中完全不注射，尽管两种基因型鼠的额叶皮质组胺释放均增加。这些结果表明，H_1R参与了从非快速眼动睡眠到清醒状态转换的调节，H_3拮抗剂的唤醒作用完全依赖于通过H_1R激活组胺能系统。给TH…注射腺苷受体激动剂CGS21680更多的大鼠基底前脑同时抑制觉醒和额叶皮质的组胺释放。用麻醉大鼠进行的微透析研究表明，A&lt；2a和gt；R激动剂可抑制大脑皮层的组胺释放，增加组胺能结节乳头核(TMN)的GABA释放，但对皮质无明显影响。向TMN内注入GABA拮抗剂印防己毒素可逆转A&lt；2A&gt；R激动剂对组胺释放的抑制作用，提示TmN的GABA能抑制作用参与了A&lt；2A&gt；R激动剂对觉醒的抑制。咖啡因是最常见的诱导清醒的物质，但参与咖啡因诱导的觉醒的受体亚型尚不清楚。当我们在WT、腺苷A_1受体(A_1R)-KO和A_1R-KO小鼠体内注射咖啡因时，咖啡因对WT和A_1R-KO小鼠有唤醒作用，而对A_1R-KO小鼠则完全无效，表明咖啡因的唤醒作用完全依赖于A_1R，而不是A_1R。较少