Artificial regulation of the sleep-wake state of an experimental animal (rat).

实验动物（大鼠）睡眠觉醒状态的人工调节。

• 批准号: 03557015
• 负责人: MATUSMURA Hitoshi
• 金额: $ 9.41万
• 依托单位: Osaka Bioscience Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03557015/
• 关键词: Prostaglandin D_2; Prostaglandin D synthase; Inorganic selenium compounds; Basal forebrain; Subarachnoid space; Continuous infusion; Microdialysis; Sleep; プロスタグランジンE_2; リポキシン; ロイコトリエン; セレン; セロトニン; プロスタグランジン; 覚醒; HMG-CoA還元酵素阻害剤; ムシモール; 不眠

The aim of this research project was to develop and establish a method of artificial regulation of the sleepwake state of an experimental animal. This project was important in achieving the ultimate purposes of our study to understand the regulatory mechanism of sleep-wake activities and consciousness and to clarify the meaning of sleep. The results of this project will be useful, as well, in developing a new medicine and/or technique for the treatment of sleep-wake disorders in man.The results of this research project indicate that, in order to artificially regulate the physiological state of sllep and wakefulness, prostaglandin (PG) D_2 and inhibitors of PGD synthase can be useful probes. When PGD_2 was infused continuously into the subarachnoid space just under the rostal basal forebrain, the slow-wave sleep extraordinarily increased up to the maximum level following a 30-min latency in rats. The sleeping state brought about by PGD_2 was indistinguishable from the natural sleep of the rats. On the other hand, when a PGD-synthase inhibitor, e.g., an inorganic quadrivalent selenium compound, was continuously administered to the rostral basal-forebrain area via a microdialysis probe that had been chronically implanted in the brain, sleep was almost completely suppressed following 2-hours latency. Such extraordinary effects could not obtained in rats with other products in the arachidonate cascade or serotonin and its related compounds, the latter of which have been actively studied for the physiological implication of serotonin in the brain sleep-wake regulatory mechanisms.Our results also indicate that not only agonists and antagonists but compounds that inhibit the PGD synthase activity also have advantages in designing new drugs of the treatment of sleep-wake disorders.

该研究项目的目的是开发和建立一种人工调节实验动物睡眠状态的方法。该项目对于实现我们研究的最终目的，即理解睡眠-觉醒活动和意识的调节机制以及阐明睡眠的意义具有重要意义。本课题的研究结果对开发治疗人类睡眠-觉醒障碍的新药物和/或新技术具有重要意义。本课题的研究结果表明，为了人工调节睡眠和觉醒的生理状态，前列腺素（PG）D_2和PGD合成酶抑制剂可以作为有用的探针。将PGD_2持续注入基底前脑喙下蛛网膜下腔，大鼠的慢波睡眠显著增加，潜伏期30 min后达到最大值。PGD_2引起的睡眠状态与大鼠的自然睡眠状态无明显区别。另一方面，当PGD合酶抑制剂，例如，通过长期植入脑中的微透析探针将无机四价硒化合物连续施用至吻侧基底前脑区，在2小时潜伏期后睡眠几乎完全被抑制。这种非凡的效果无法在大鼠中获得花生四烯酸级联反应中的其他产物或血清素及其相关化合物，后者已被积极研究，以了解血清素在大脑睡眠中的生理意义-我们的结果还表明，不仅激动剂和拮抗剂，而且抑制PGD合酶活性的化合物在设计治疗PGD的新药方面也具有优势。睡眠-觉醒障碍

项目成果

S.Sri Kantha, H.Matsumura, E.Kubo, K.Kawase, R.Takahata, C.N.Serhan, O.Hayaishi: "Effects of prostaglandin D_2, lipoxins and leukotrienes on sleep and brain temperature of rats." Prostaglandins Leukotrienes and Essential Fatty Acids. 51. 87-93 (1994)

S.Sri Kantha、H.Matsumura、E.Kubo、K.Kawase、R.Takahata、C.N.Serhan、O.Hayaishi：“前列腺素 D_2、脂氧素和白三烯对大鼠睡眠和脑温度的影响。”

Matsumura,H.: "Inhibition of sleep in rats by inorganic selenium compounds,inhibitors of prostaglandin D synthase" Proc.Natl.Acad.Sci.USA. 88. 9046-9050 (1991)

Matsumura, H.：“无机硒化合物、前列腺素 D 合酶抑制剂对大鼠睡眠的抑制”Proc.Natl.Acad.Sci.USA。

Matsumura,H.: "Site of action for the sleep-promoting,effect of prostaglandin D_2:Examination in freely-behaving rats by bilateral administration using microdialysis techenique." Jpn.J.Psychiatr.Neurol.(Proceeding). (in press).

Matsumura,H.：“前列腺素 D_2 促进睡眠的作用位点：使用微透析技术通过双侧给药对自由行为的大鼠进行检查。”

早石修,松村人志(睡眠の分子機構)(総説): "分子神経科学の最先端" 岡田善雄監修,遠山正彌編集,厚生社(印刷中), (1994)

Osamu Hayaishi、Hitoshi Matsumura（睡眠的分子机制）（评论）：“分子神经科学的前沿”，由冈田义夫监督，由 Masaya Toyama 编辑，Koshosha（出版中），（1994 年）

Hitoshi Matsumura, Tomoko Nakajima, Toshimasa Osaka, Shinsuke Satoh, Kumiko Kawase, Etsuko Kubo, Sachi Sri Kantha, Keiko Kasahara, Osamu Hayaishi: "Prostaglandin D_2-sensitive, sleep-promoting zone defined in the ventral surface of the rostral basal foreb

Hitoshi Matsumura、Tomoko Nakajima、Toshimasa Osaka、Shinsuke Satoh、Kumiko Kawase、Etsuko Kubo、Sachi Sri Kantha、Keiko Kasahara、Osamu Hayaishi：“前列腺素 D_2 敏感、促进睡眠的区域定义在前臂基底腹侧表面