Promotion of non-rapid eye movement sleep and activation of reticular thalamic neurons by a novel MT ₂ 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 notMT 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 MT2 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.