MT-2 -: Differential Function of Melatonin MT 1 and MT 2 Receptors in REM and NREM Sleep.

The pathophysiological function of the G-protein coupled melatonin MT 1 and MT 2 receptors has not yet been well-clarified. Recent advancements using selective MT 1 / MT 2 receptor ligands and MT 1 /MT 2 receptor knockout mice have suggested that the activation of the MT 1 receptors are mainly implicated in the regulation of rapid eye movement (REM) sleep, whereas the MT 2 receptors selectively increase non-REM (NREM) sleep. Studies in mutant mice show that MT 1 knockout mice have an increase in NREM sleep and a decrease in REM sleep, while MT2 knockout mice a decrease in NREM sleep. The localization of MT 1 receptors is also distinct from MT2 receptors; for example, MT 2 receptors are located in the reticular thalamus (NREM area), while the MT 1 receptors in the Locus Coeruleus and lateral hypothalamus (REM areas). Altogether, these findings suggest that these two receptors not only have a very specialized function in sleep, but that they may also modulate opposing effects. These data also suggest that mixed MT 1 -MT 2 receptors ligands are not clinically recommended given their opposite roles in physiological functions, confirmed by the modest effects of melatonin or MT 1 /MT 2 non-selective agonists when used in both preclinical and clinical studies as hypnotic drugs. In sum, MT 1 and MT 2 receptors have specific roles in the modulation of sleep, and consequently, selective ligands with agonist, antagonist, or partial agonist properties could have therapeutic potential for sleep; while the MT 2 agonists or partial agonists might be indicated for NREM-related sleep and/or anxiety disorders, the MT 1 agonists or partial agonists might be so for REM-related sleep disorders. Furthermore, MT 1 but not MT 2 receptors seem involved in the regulation of the circadian rhythm. Future research will help further develop MT 1 and/or MT 2 receptors as targets for neuropsychopharmacology drug development.