Molecular mechanism of wakefulness regulation

在基线条件下，组胺H_1受体（H_1R）基因敲除（KO）小鼠的睡眠-觉醒周期与野生型（WT）小鼠基本相同，但在非快速眼动（NREM）睡眠期间短暂觉醒（<16秒）的事件较少，且在腹腔注射生理盐水后启动NREM睡眠的潜伏期较短。H_1R拮抗剂吡拉明在WT小鼠中可模拟这些作用。组胺H_3受体拮抗剂环丙昔芬（ciproxifan）可增加WT小鼠的觉醒，但对H_1R KO小鼠无明显影响，且呈剂量依赖性。这些结果表明H_1R参与了NREM睡眠到觉醒的调节，H_3受体拮抗剂的觉醒效应完全依赖于H_1R对组胺能系统的激活<2A><2A> ...更多信息 大鼠基底前脑抑制觉醒和额叶皮质组胺释放。麻醉大鼠微透析实验表明，A_<2A>R激动剂能抑制皮质组胺释放，增加结节乳头核（TMN）的GABA释放，但对皮质无影响。TMN<2A>内注射GABA拮抗剂印防己毒素可逆转A_R激动剂对组胺释放的抑制作用，表明A_R激动剂对TMN的GABA能抑制参与了觉醒的抑制<2A>。咖啡因是最常见的致醒物质，但参与咖啡因致醒的受体亚型尚不清楚。在WT、腺苷A_1受体（A_1R）-KO和A_ R-KO小鼠中给予咖啡因后<2A>，咖啡因对WT和A_1 R-KO小鼠有觉醒作用，而对A_<2A>R-KO小鼠无觉醒作用，表明咖啡因的觉醒作用完全依赖于A_<2A>R，而不依赖于A_1 R。少

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