Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice
Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice
复制标题
组胺 H1 受体敲除小鼠的睡眠-觉醒特征发生改变，且对 H3 受体拮抗剂缺乏唤醒反应。
DOI：
10.1073/pnas.0600451103
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发表时间：
2006-03-21
影响因子：
11.1
通讯作者：
Hayaishi, O
中科院分区：
文献类型：
--
作者：
Huang, ZL;Mochizuki, T;Hayaishi, O
组胺能神经元通过组胺H(1)受体（H(1)R）在调节睡眠-觉醒行为中发挥重要作用。提出阻断组胺H(3)受体（H(3)R）通过调节各种与觉醒相关的递质的释放来诱导觉醒，而不仅仅是组胺。在本研究中，我们描述了H(1)R敲除（KO）小鼠的睡眠-觉醒周期以及它们对H(3)R拮抗剂的觉醒反应。在基线条件下，H(1)R KO小鼠的睡眠-觉醒周期与WT小鼠基本相同，但短暂觉醒（<16秒）的事件较少，非快速眼动（NREM）睡眠发作的持续时间较长，非快速眼动睡眠和清醒之间的状态转换次数减少，并且在口服生理盐水后启动NREM睡眠的潜伏期较短。H(1)R拮抗剂吡咯胺在WT小鼠中模拟了这些作用。当口服H(3)R拮抗剂环丙昔芬时，WT小鼠的清醒程度呈剂量依赖性增加，而H(1)R KO小鼠的清醒程度则完全没有增加。体内微透析显示，在两种基因型小鼠中，口服环丙昔芬增加了额叶皮层的组胺释放。这些结果表明，H(1)R参与了从NREM睡眠到清醒的行为状态转换的调节，H(3)R拮抗剂的唤醒作用完全依赖于H(1)R对组胺能系统的激活。
Histaminergic neurons play an important role in the regulation of sleep-wake behavior through histamine H(1) receptors (H(1)R). Blockade of the histamine H(3) receptor (H(3)R) is proposed to induce wakefulness by regulating the release of various wake-related transmitters, not only histamine. In the present study, we characterized sleep-wake cycles of H(1)R knockout (KO) mice and their arousal responses to an H(3)R antagonist. Under baseline conditions, H(1)R KO mice showed sleep-wake cycles essentially identical to those of WT mice but with fewer incidents of brief awakening (<16-sec epoch), prolonged durations of non-rapid eye movement (NREM) sleep episodes, a decreased number of state transitions between NREM sleep and wakefulness, and a shorter latency for initiating NREM sleep after an i.p. injection of saline. The H(1)R antagonist pyrilamine mimicked these effects in WT mice. When an H(3)R antagonist, ciproxifan, was administered i.p., wakefulness increased in WT mice in a dose-dependent manner but did not increase at all in H(1)R KO mice. In vivo microdialysis revealed that the i.p. application of ciproxifan increased histamine release from the frontal cortex in both genotypes of mice. These results indicate that H(1)R is involved in the regulation of behavioral state transitions from NREM sleep to wakefulness and that the arousal effect of the H(3)R antagonist completely depends on the activation of histaminergic systems through H(1)R.