Hypothalamic arousal regions are activated during modafinil-induced wakefulness
Hypothalamic arousal regions are activated during modafinil-induced wakefulness
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DOI：
10.1523/jneurosci.20-22-08620.2000
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发表时间：
2000-11-15
影响因子：
5.3
通讯作者：
Saper, CB
中科院分区：
文献类型：
--
作者：
Scammell, TE;Estabrooke, IV;Saper, CB
莫达非尼是一种越来越受欢迎的促进清醒的药物，用于治疗嗜睡症，但其确切的作用机制尚不清楚。为了确定莫达非尼作用的潜在途径，我们给大鼠注射了一定剂量的莫达非尼，记录了睡眠/清醒活动，并使用Fos免疫组织化学研究了神经元激活模式。为了对比莫达非尼诱导的清醒和自发的清醒，我们在大鼠正常清醒的午夜给药莫达非尼。为了确定昼夜节律阶段或环境光的影响，我们还在正常光/暗周期或持续黑暗的中午注射莫达非尼。我们发现，75 mg/kg莫达非尼增加了皮质周围区结节乳头核（TMN）和食欲素（下丘脑分泌素）神经元的Fos免疫反应性，这两个细胞组与觉醒调节有关。这种低剂量的莫达非尼也增加了杏仁核中央核外侧亚区Fos-IR神经元的数量。更高的剂量增加了纹状体和扣带皮层中Fos-IR神经元的数量。与以往的研究相比，莫达非尼在视交叉上核和下丘脑前区均未引起Fos表达的统计学显著增加。这些观察结果表明，莫达非尼可能通过激活颞叶神经网络和食欲素神经元来促进清醒，这两个区域与促进正常清醒有关。这些下丘脑区域的选择性药理激活可能代表了一种诱导觉醒的新方法。
Modafinil is an increasingly popular wake-promoting drug used for the treatment of narcolepsy, but its precise mechanism of action is unknown. To determine potential pathways via which modafinil acts, we administered a range of doses of modafinil to rats, recorded sleep/wake activity, and studied the pattern of neuronal activation using Fos immunohistochemistry. To contrast modafinil-induced wakefulness with spontaneous wakefulness, we administered modafinil at midnight, during the normal waking period of rats. To determine the influence of circadian phase or ambient light, we also injected modafinil at noon on a normal light/dark cycle or in constant darkness. We found that 75 mg/kg modafinil increased Fos immunoreactivity in the tuberomammillary nucleus (TMN) and in orexin (hypocretin) neurons of the perifornical area, two cell groups implicated in the regulation of wakefulness. This low dose of modafinil also increased the number of Fos-immunoreactive (Fos-IR) neurons in the lateral subdivision of the central nucleus of the amygdala. Higher doses increased the number of Fos-IR neurons in the striatum and cingulate cortex. In contrast to previous studies, modafinil did not produce statistically significant increases in Fos expression in either the suprachiasmatic nucleus or the anterior hypothalamic area. These observations suggest that modafinil may promote waking via activation of TMN and orexin neurons, two regions implicated in the promotion of normal wakefulness. Selective pharmacological activation of these hypothalamic regions may represent a novel approach to inducing wakefulness.