title: Promotion of non-rapid eye movement sleep and activation of reticular thalamic neurons by a novel MT2 melatonin receptor ligand.
abstract: 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.
authors.affiliation: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ochoa-Sanchez
authors.forename: Stefano
authors.initials: S
authors.lastname: Comai
authors.forename: Baptiste
authors.initials: B
authors.lastname: Lacoste
authors.forename: Francis Rodriguez
authors.initials: FR
authors.lastname: Bambico
authors.forename: Sergio
authors.initials: S
authors.lastname: Dominguez-Lopez
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Debora
authors.initials: D
authors.lastname: Angeloni
authors.forename: Franco
authors.initials: F
authors.lastname: Fraschini
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Laurent
authors.initials: L
authors.lastname: Descarries
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gobbi
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044123:Receptor, Melatonin, MT2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects*; D013788:Thalamus / Q000187:drug effects*
chemical_list: D000081:Acetamides; D000814:Aniline Compounds; C545680:N-(2-((3-methoxyphenyl)phenylamino)ethyl)acetamide; D044123:Receptor, Melatonin, MT2