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

本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。这个项目对于实现我们研究的最终目的，了解睡眠-觉醒活动和意识的调节机制，以及澄清睡眠的意义具有重要意义。这项研究的结果也将有助于开发治疗人类睡眠-觉醒障碍的新药物和/或技术。本研究结果表明，为了人工调节睡眠和觉醒的生理状态，前列腺素D_2和前列腺素D合成酶抑制剂可以成为有用的探针。将PGD_2持续注入大鼠头侧基底前脑正下方蛛网膜下腔，大鼠慢波睡眠在潜伏期30min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，当一种PGD-合成酶抑制剂，例如一种无机的四价硒化合物，通过一个长期植入大脑的微透析探针被持续地注入到头端的基底前脑区域时，在2小时的潜伏期后，睡眠几乎完全被抑制。在其他花生四烯酸级联产物或5-羟色胺及其相关化合物中，大鼠无法获得这种特殊的效果，后者已被积极研究5-羟色胺在大脑睡眠-觉醒调节机制中的生理意义。我们的结果还表明，不仅激动剂和拮抗剂，而且抑制PGD合成酶活性的化合物在设计治疗睡眠-唤醒障碍的新药方面也具有优势。

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.