Melatonin recovers sleep phase delayed by MK‐801 through the melatonin MT2 receptor‐ Ca2+‐CaMKII‐CREB pathway in the ventrolateral preoptic nucleus

作者：Qian Wang, Dexiao Zhu, Shuo Ping, Chuangang Li, Kunkun Pang, Shaowei Zhu, Jing Zhang, Stefano Comai, Jinhao Sun · 发表于：Journal of Pineal Research · 年份：2020 · DOI：10.1111/jpi.12674 · 被引用次数：20 · 研究领域：Circadian rhythm and melatonin、Sleep and Wakefulness Research、Photoreceptor and optogenetics research

Abstract Melatonin (MLT) is widely used to treat sleep disorders although the underlying mechanism is still elusive. In mice, using wheel‐running detection, we found that exogenous MLT could completely recover the period length prolonged by N‐methyl‐D‐aspartate receptor (NMDAR) impairment due to the injection of the NMDAR antagonist MK‐801, a preclinical model of psychosis. The analysis of the possible underlying mechanisms indicated that MLT could regulate the homeostatic state in the ventrolateral preoptic nucleus (VLPO) instead of the circadian process in the suprachiasmatic nucleus (SCN). In addition, our data showed that MK‐801 decreased Ca 2+ ‐related CaMKII expression and CREB phosphorylation levels in the VLPO, and MLT could rescue these intracellular impairments but not NMDAR expression levels. Accordingly, Gcamp6 AAV virus was injected in‐vivo to further monitor intracellular Ca 2+ levels in the VLPO, and MLT demonstrated a unique ability to increase Ca 2+ fluorescence compared with MK‐801‐injected mice. Additionally, using the selective melatonin MT 2 receptor antagonist 4‐phenyl‐2‐propionamidotetralin (4P‐PDOT), we discovered that the pharmacological effects of MLT upon NMDAR impairments were mediated by melatonin MT 2 receptors. Using electroencephalography/electromyography (EEG/EMG) recordings, we observed that the latency to the first nonrapid eye movement (NREM) sleep episode was delayed by MK‐801, and MLT was able to recover this delay. In conclusion, exogeno...