Crosstalk of signal transduction in sleep-wake regulation

给药SeC14，一种前列腺素（PG） D合成酶（PGDS）的选择性抑制剂，在野生型或造血PGDS敲除（KO）小鼠中呈剂量依赖性地抑制睡眠，但在脂质钙素型PGDS KO、造血和脂质钙素型PGDS双KO或PGD受体（DP1R） KO小鼠中完全没有抑制作用。此外，DP1R拮抗剂在基底前脑吻侧下的蛛网膜下腔注入时减少了大鼠的睡眠。这些结果清楚地表明，脂脂素型PGDS/PGD2/DP1R系统在生理睡眠的调节中起着关键作用。PGD_2通过激活腹外侧视前区的睡眠中心和抑制组胺能结节乳头核（TMN）的觉醒中心来促进睡眠。当我们检测组胺H_1受体（H_1R） KO小鼠的睡眠-觉醒周期时，H_1R KO小鼠的睡眠-觉醒周期较少，表明H_1R参与了从非快速眼动（NREM）睡眠到觉醒的行为状态转换的调节。组胺能TMN含有腺苷脱氨酶。抑制TMN中腺苷脱氨酶或激活腺苷A_1受体可增加NREM睡眠，抑制脑内组胺释放。这些结果表明腺苷抑制组胺能活性并通过A_1受体诱导NREM睡眠。莫达非尼的唤醒作用与组胺能系统有关。然而，我们发现莫达非尼在H_1R KO和野生型小鼠中都能诱导清醒，这表明组胺能系统对莫达非尼诱导的清醒不是必需的。然而，多巴胺d2受体KO小鼠表现出减弱的莫达非尼诱导的觉醒。此外，用Di受体拮抗剂预处理d2受体KO小鼠可完全消除莫达非尼的唤醒作用。这些结果表明，多巴胺能D_1和D_2受体在莫达非尼引起的清醒中起重要作用。

Administration of SeC14, a selective inhibitor of prostaglandin (PG) D synthase (PGDS), inhibited sleep dose-dependently in wild-type or hematopoietic PGDS knockout (KO) mice but not at all in lipocalin-type PGDS KO, hematopoietic and lipocalin-type PGDS double KO or PGD receptor (DP1R) KO mice. Furthermore, the DP1R antagonist reduced sleep of rats during infusion into the subarachnoid space under the rostral basal forebrain. These results clearly show that lipocalin-type PGDS/PGD2/DP1R system plays pivotal roles in the regulation of physiological sleep.PGD_2 promotes sleep by activation of a sleep-center in the ventrolateral pre-optic area, and suppression of the wake-center in the histaminergic tuberomammillary nucleus (TMN). When we examined sleep-wake cycles of histamine H_1 receptors (H_1R) KO mice, H_1R KO mice showed sleep-wake cycles with fewer incidents of brief awakening, indicating that H_1R was involved in the regulation of behavioral state transitions from non-rapid eye movement (NREM) sleep to wakefulness.Histaminergic TMN contains adenosine deaminase. Inhibition of adenosine deaminase or activation of adenosine A_1 receptor in the TMN increased NREM sleep and suppressed the histamine release in the brain. These results that indicate adenosine suppresses histaminergic activity and induces NREM sleep via A_1 receptors.Histaminergic system had been implicated in the arousal effect of modafinil. However, we found that modafinil induced wakefulness in both H_1R KO and wild-type mice, indicating that histaminergic system was not essential for the modafinil-induced wakefulness. However, dopamine D_2 receptor KO mice exhibited attenuated modafinil-induced wakefulness. Moreover, pretreatment of D_2 receptor KO mice with Di receptor antagonist completely abolished arousal effects of modafinil. These findings indicate that the dopaminergic D_1 and D_2 receptor are essential for the wakefulness induced by modafinil.