Promotion of non-rapid eye movement sleep and activation of reticular thalamic neurons by a novel MT2 melatonin receptor ligand.

Melatonin activates two brain G-protein coupled receptors, MT(1) and MT(2), whose differential roles in the sleep-wake cycle remain to be defined. The novel MT(2) receptor partial agonist, N-{2-[(3-methoxyphenyl) phenylamino] ethyl} acetamide (UCM765), is here shown to selectively promote non-rapid eye movement sleep (NREMS) in rats and mice. The enhancement of NREMS by UCM765 is nullified by the pharmacological blockade or genetic deletion of MT(2) receptors. MT(2), but not MT(1), knock-out mice show a decrease in NREMS compared to the wild strain. Immunohistochemical labeling reveals that MT(2) receptors are localized in sleep-related brain regions, and notably the reticular thalamic nucleus (Rt). Microinfusion of UCM765 in the Rt promotes NREMS, and its systemic administration induces an increase in firing and rhythmic burst activity of Rt neurons, which is blocked by the MT(2) antagonist 4-phenyl-2-propionamidotetralin. Since developing hypnotics that increase NREMS without altering sleep architecture remains a medical challenge, MT(2) receptors may represent a novel target for the treatment of sleep disorders.
AuthorsRafael Ochoa-Sanchez, Stefano Comai, Baptiste Lacoste, Francis Rodriguez Bambico, Sergio Dominguez-Lopez, Gilberto Spadoni, Silvia Rivara, Annalida Bedini, Debora Angeloni, Franco Fraschini, Marco Mor, Giorgio Tarzia, Laurent Descarries, Gabriella Gobbi
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 31 Issue 50 Pg. 18439-52 (Dec 14 2011) ISSN: 1529-2401 [Electronic] United States
PMID22171046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Acetamides
  • Aniline Compounds
  • N-(2-((3-methoxyphenyl)phenylamino)ethyl)acetamide
  • Receptor, Melatonin, MT2
  • Acetamides (pharmacology)
  • Aniline Compounds (pharmacology)
  • Animals
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Neurons (drug effects)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Melatonin, MT2 (agonists, genetics, metabolism)
  • Sleep (drug effects)
  • Thalamus (drug effects)

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