Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT₁ receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT₁ receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT₁ pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT₁ receptors in the LC-NE neurons. In conclusion, MT₁ receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.

睡眠障碍影响着全世界数百万人，并且与精神疾病有很高的共病率。虽然目前的催眠药大多会增加非快速眼动睡眠（NREMS），但缺乏选择性地增强快速眼动睡眠（REMS）的药物。这项针对雄性大鼠的多导睡眠图研究表明，一流的选择性褪黑激素 MT ₁受体部分激动剂 UCM871 可以延长 REMS 的持续时间，而不影响 NREMS 的持续时间。 UCM871 的 REMS 促进作用是通过以剂量反应方式抑制表达 MT ₁受体的蓝斑 (LC) 去甲肾上腺素 (NE) 神经元的放电活动来实现的。 REMS 持续时间的增加和 UCM871 对 LC-NE 神经元活性的抑制被 MT ₁药理学拮抗作用和腺相关病毒 (AAV) 载体所消除，该载体选择性地敲低 LC-NE 神经元中的 MT ₁受体。总之，MT ₁受体激动剂抑制 LC-NE 神经元并触发 REMS，从而代表 REMS 疾病和/或与 REMS 损伤相关的精神疾病的新机制和靶点。