Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction
Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction
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DOI：
10.1111/j.1460-9568.2006.05019.x
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发表时间：
2006-09-01
影响因子：
3.4
通讯作者：
Porkka-Heiskanen, T.
中科院分区：
文献类型：
--
作者：
Kalinchuk, A. V.;Stenberg, D.;Porkka-Heiskanen, T.
睡眠内稳态是通过延长的觉醒产生恢复性睡眠的过程。这一重要现象背后的分子机制知之甚少。我们以前已经表明，一氧化氮（NO）的产生增加，在基底前脑（BF）在睡眠剥夺（SD）。此外，NO合酶（NOS）抑制和NO清除剂防止恢复睡眠诱导，而在自发的睡眠-觉醒周期期间的NO供体的管理增加睡眠，表明NO是必要的和足够的诱导恢复睡眠。接下来，我们想知道哪种NOS亚型参与了恢复性睡眠的产生。采用在体微透析技术，将特异性NOS抑制剂注入SD大鼠BF，发现诱导型NOS（iNOS）抑制剂1400 W可抑制非快速眼动（NREM）的恢复，而神经型NOS（nNOS）抑制剂L-N-丙基精氨酸（L-N-propyl-arginine）可抑制REM的恢复，但不影响NREM的恢复。使用免疫印迹分析，我们发现，诱导型一氧化氮合酶不表达在自发的睡眠-觉醒周期，但诱导延长觉醒（增加了278%）。一种已知的诱导型一氧化氮合酶的诱导剂，脂多糖，引起睡眠的增加，非常类似于恢复睡眠，其影响被1400 W消除。这些结果表明，诱导诱导型一氧化氮合酶在BF在长时间觉醒的升高是一个特定的机制，产生NREM恢复睡眠，这两个NOS亚型有一个互补的作用，NREM和REM恢复诱导。
Sleep homeostasis is the process by which recovery sleep is generated by prolonged wakefulness. The molecular mechanisms underlying this important phenomenon are poorly understood. We have previously shown that nitric oxide (NO) generation increases in the basal forebrain (BF) during sleep deprivation (SD). Moreover, both NO synthase (NOS) inhibition and a NO scavenger prevented recovery sleep induction, while administration of a NO donor during the spontaneous sleep-wake cycle increased sleep, indicating that NO is necessary and sufficient for the induction of recovery sleep. Next we wanted to know which NOS isoform is involved in the production of recovery sleep. Using in vivo microdialysis we infused specific inhibitors of NOS into the BF of rats during SD, and found that an inhibitor of inducible NOS (iNOS), 1400W, prevented non-rapid eye movement (NREM) recovery, while an inhibitor of neuronal NOS (nNOS), L-N-propyl-arginine, decreased REM recovery but did not affect NREM recovery. Using immunoblot analysis we found that iNOS was not expressed during the spontaneous sleep-wake cycle, but was induced by prolonged wakefulness (increased by 278 %). A known iNOS inducer, lipopolysaccharide, evoked an increase in sleep that closely resembled recovery sleep, and its effects were abolished by 1400W. These results suggest that the elevation of NO produced by induction of iNOS in the BF during prolonged wakefulness is a specific mechanism for producing NREM recovery sleep and that the two NOS isoforms have a complementary role in NREM and REM recovery induction.