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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.

Differential Function of Melatonin MT1 and MT2 Receptors in REM and NREM Sleep