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

Qian Wang, Dexiao Zhu, Shuo Ping, Chuangang Li, Kunkun Pang, Shaowei Zhu, Jing Zhang, Stefano Comai, Jinhao Sun

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 Ca2+-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 Ca2+ levels in the VLPO, and MLT demonstrated a unique ability to increase Ca2+ fluorescence compared with MK-801-injected mice. Additionally, using the selective melatonin MT2 receptor antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT), we discovered that the pharmacological effects of MLT upon NMDAR impairments were mediated by melatonin MT2 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 MT2 receptors rescues sleep phase delayed by NMDAR impairment via increasing intracellular Ca2+ signaling in the VLPO, suggesting a regulatory role of the neurohormone on the homeostatic system.

Original languageEnglish (US)
Article numbere12674
JournalJournal of pineal research
Volume69
Issue number3
DOIs
StatePublished - Oct 1 2020
Externally publishedYes

Keywords

  • MT receptors
  • NMDA receptors
  • calcium
  • homeostatic mechanism
  • melatonin
  • sleep

ASJC Scopus subject areas

  • Endocrinology

Fingerprint

Dive into the research topics of 'Melatonin recovers sleep phase delayed by MK-801 through the melatonin MT2 receptor- Ca2+-CaMKII-CREB pathway in the ventrolateral preoptic nucleus'. Together they form a unique fingerprint.

Cite this