Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep
Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep
复制标题
DOI：
10.1073/pnas.0810926105
复制
发表时间：
2008-12-16
影响因子：
11.1
通讯作者：
Hayaishi, Osamu
中科院分区：
文献类型：
--
作者：
Oishi, Yo;Huang, Zhi-Li;Hayaishi, Osamu
腺苷被认为通过大脑中的A(1)受体(A(1)R‘s)和/或A(2A)受体促进睡眠。我们先前报道，A(2A)受体介导内源性睡眠诱导物质前列腺素D-2的睡眠促进作用，这些受体的激活诱导睡眠，并被咖啡因阻断导致觉醒。另一方面，A(1)R被认为通过抑制基底前脑的胆碱能区来增加睡眠。然而，A(1)R在睡眠-觉醒调节中的作用和靶点仍然存在争议。免疫组织化学显示A(1)R在大鼠结节乳头核(TMN)的组胺能神经元中有表达。在体微透析显示，向TMN内微量注射A(1)R激动剂N-6-环戊基腺苷(CPA)、腺苷脱氨酶抑制剂腺苷或将腺苷分解为肌苷的甲钴素，可减少额叶皮质组胺的释放。大鼠双侧TMN注射CPA可显着增加非快速眼动(non-REM；NREM)睡眠的数量和增量功率密度，但不影响REM睡眠。在WT小鼠中观察到CPA促进的睡眠，而在KO小鼠中未观察到A(1)R或组胺H-1受体的促进睡眠，表明A(1)R特异性激动剂促进的NREM睡眠依赖于组胺能系统。此外，双侧TMN内注射腺苷或考福霉素可增加大鼠的NREM睡眠，而选择性A(1)R拮抗剂1，3-二甲基-8-环烯丙基黄嘌呤可完全阻断这一睡眠。这些结果表明，TMN中的内源性腺苷通过A(1)R抑制组胺能系统，从而促进NREM睡眠。
Adenosine has been proposed to promote sleep through A(1) receptors (A(1)R's) and/or A(2A) receptors in the brain. We previously reported that A(2A) receptors mediate the sleep-promoting effect of prostaglandin D-2, an endogenous sleep-inducing substance, and that activation of these receptors induces sleep and blockade of them by caffeine results in wakefulness. On the other hand, A(1)R has been suggested to increase sleep by inhibition of the cholinergic region of the basal forebrain. However, the role and target sites of A(1)R in sleep-wake regulation remained controversial. In this study, immunohistochemistry revealed that A(1)R was expressed in histaminergic neurons of the rat tuberomammillary nucleus (TMN). In vivo microdialysis showed that the histamine release in the frontal cortex was decreased by microinjection into the TMN of N-6-cyclopentyladenosine (CPA), an A(1)R agonist, adenosine or coformycin, an inhibitor of adenosine deaminase, which catabolizes adenosine to inosine. Bilateral injection of CPA into the rat TMN significantly increased the amount and the delta power density of non-rapid eye movement (non-REM; NREM) sleep but did not affect REM sleep. CPA-promoted sleep was observed in WT mice but not in KO mice for A(1)R or histamine H-1 receptor, indicating that the NREM sleep promoted by A(1)R-specific agonist depended on the histaminergic system. Furthermore, the bilateral injection of adenosine or coformycin into the rat TMN increased NREM sleep, which was completely abolished by coadministration of 1,3-dimethyl-8-cyclopenthylxanthine, a selective A(1)R antagonist. These results indicate that endogenous adenosine in the TMN suppresses the histaminergic system via A(1)R to promote NREM sleep.