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Melatonin recovers sleep phase delayed by MK‐801 through the melatonin MT 2 receptor‐ Ca 2+ ‐CaMKII‐CREB pathway in the ventrolateral preoptic nucleus
Author(s) -
Wang Qian,
Zhu Dexiao,
Ping Shuo,
Li Chuangang,
Pang Kunkun,
Zhu Shaowei,
Zhang Jing,
Comai Stefano,
Sun Jinhao
Publication year - 2020
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12674
Subject(s) - melatonin , nmda receptor , medicine , suprachiasmatic nucleus , melatonin receptor , endocrinology , creb , receptor , neuroscience , chemistry , biology , hypothalamus , biochemistry , transcription factor , gene
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, exogenous MLT by acting upon melatonin MT 2 receptors rescues sleep phase delayed by NMDAR impairment via increasing intracellular Ca 2+ signaling in the VLPO, suggesting a regulatory role of the neurohormone on the homeostatic system.