Studies on the role of orexin in the brain vigilance levels.

研究食欲素在大脑警觉水平中的作用。

• 批准号: 11670934
• 负责人: HONDA Kazuki
• 金额: $ 2.11万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670934/
• 关键词: Orexin; Narcolepsy; non-REM sleep; REM sleep; Sleep-waking system; Dopamine; 覚醒維持機構; 睡眠・覚醒調節

Orexins A and B are novel neuropeptides which are known to regulate the appetite system. Recent studies showed that canine narcolepsy is caused by deficit in the orexin-2 receptor gene, and that prepro-orexin knock-out mice exhibited similar behavior to human and canine narcoleptics. Orexin-containing neurons are localized in the lateral hypothalamic area and densely project to the noradrenergic locus coeruleus, dopaminergic ventral tegmental area, serotonergic dorsal raphe nuclei and histaminergic tuberomammillary nucleus. Intracerebroventricular (icv) infusion of orexins A and B induced significant arousal effect in the freely behaving normal-male Sprague-Dawley rats. Cortical EEG and neck EMG were monitored for three consecutive days , during continuous icv saline infusion at a rate of 10 μl/h. For 5-h diurnal period, either orexin A (0.1-10 nmol) or B ( 1-40 nmol) replaced. the icv infusion of saline. Orexin A at the dose of 10 nmol markedly increased the amount of wakefulness by 228.6% (p<0.01) whereas orexin B at the same dose caused an increase of 99.8% (p<0.01) over the baseline value. Both orexins caused dose-dependent increases in wakefulness. The enhancement of arousal was due to a marked reduction in sleep. The data indicate that orexin A is more effective in causing a state of arousal than orexin B at the same dose. Since orexin A has equal affinity for both the orexin-1 and orexin-2 receptors but orexin B only shows affinity for the orexin-2 receptor, thus exogenous administration of orexin A might be more effective in enhancing a state of arousal than orexin B.In conclusion, the results suggest that orexins A and B may play important physiological roles in the regulation of sleep-waking cycle through both the orexin-1 and orexin-2 receptor sites.

食欲素A和B是已知调节食欲系统的新型神经肽。最近的研究表明，犬发作性睡病是由食欲素-2受体基因缺陷引起的，并且前食欲素原基因敲除小鼠表现出与人类和犬发作性睡病相似的行为。含食欲素的神经元位于下丘脑外侧区，密集地投射到去甲肾上腺素能蓝斑、多巴胺能腹侧被盖区、多巴胺能中缝背核和组胺能结节乳头核。侧脑室（icv）灌注食欲素A和B在自由行为的正常雄性Sprague-Dawley大鼠中诱导显著的唤醒效应。连续3天监测皮层脑电图和颈部肌电图，同时以10 μl/h速率持续icv输注生理盐水。在5小时的昼夜周期内，Orexin A（0.1-10 nmol）或B（1-40 nmol）被替换。icv输注生理盐水。在10 nmol剂量下的食欲素A使觉醒量显著增加228.6%（p<0.01），而在相同剂量下的食欲素B引起比基线值增加99.8%（p<0.01）。这两种食欲素都引起了剂量依赖性的觉醒增加。觉醒的增强是由于睡眠的显着减少。数据表明，在相同剂量下，食欲素A比食欲素B更有效地引起唤醒状态。由于食欲素A对食欲素-1和食欲素-2受体具有相等的亲和力，但食欲素B仅显示对食欲素-2受体的亲和力，因此食欲素A的外源性施用可能比食欲素B更有效地增强唤醒状态。这些结果提示，食欲素A和B可能通过食欲素1和食欲素2在睡眠-觉醒周期的调节中发挥重要的生理作用。2个受体位点。

项目成果

Honda K,Akanmu M,Mochizuki T,Inoue S: "Orexin promotes wakefulness in the freely behaving rats"Sleep. 24(inpress). (2001)

Honda K、Akanmu M、Mochizuki T、Inoue S：“食欲素促进自由行为大鼠的觉醒”睡眠。

Inoue S,Honda K: "Vitamin B12 promotes sleep and modulates the circadian rhythm of sleep and brain temperature in rats."Sleep and Hypnosis. 1. 98-104 (1999)

Inoue S、Honda K：“维生素 B12 促进睡眠并调节大鼠睡眠的昼夜节律和脑温度。”睡眠与催眠。

Honda K, Reihl J, Mignot E, Nishino S.: "Dopamine D3 agonists into the substantia nigra aggravate cataplexy but do not modify sleep."NeuroReport. 10. 3717-3724 (1999)

Honda K、Reihl J、Mignot E、Nishino S.：“多巴胺 D3 激动剂进入黑质会加重猝倒，但不会改变睡眠。”NeuroReport。

Honda K, Lee SP, Inoue S.: "Syringin enhances slow wave sleep in unrestrained rats."Rep Inst Biomatr Bioeng. 33. 75-79 (1999)

Honda K、Lee SP、Inoue S.：“紫丁香苷可增强不受约束的大鼠的慢波睡眠。”Rep Inst Biomatr Bioeng。

Riehl J, Honda K, Hong J, Kwan M, Mignot E, Nishino S: "Chronic oral administration of CG-3703, a thyrotropin releasing hormone analog, increases wake and decreases cataplexy in canine narcolepsy."Neuropsycopharmacology. 23. 34-45 (2000)

Riehl J、Honda K、Hong J、Kwan M、Mignot E、Nishino S：“长期口服 CG-3703（一种促甲状腺激素释放激素类似物）可增加犬发作性睡病的觉醒并减少猝倒。”神经精神药理学。