AUTHOR=Gobbi Gabriella , Comai Stefano 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00087

DOI=10.3389/fendo.2019.00087

ISSN=1664-2392

ABSTRACT=<p>The pathophysiological function of the G-protein coupled melatonin MT<sub>1</sub> and MT<sub>2</sub> receptors has not yet been well-clarified. Recent advancements using selective MT<sub>1</sub>/ MT<sub>2</sub> receptor ligands and MT<sub>1</sub>/MT<sub>2</sub> receptor knockout mice have suggested that the activation of the MT<sub>1</sub> receptors are mainly implicated in the regulation of rapid eye movement (REM) sleep, whereas the MT<sub>2</sub> receptors selectively increase non-REM (NREM) sleep. Studies in mutant mice show that MT<sub>1</sub> 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<sub>1</sub> receptors is also distinct from MT2 receptors; for example, MT<sub>2</sub> receptors are located in the reticular thalamus (NREM area), while the MT<sub>1</sub> 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<sub>1</sub>-MT<sub>2</sub> receptors ligands are not clinically recommended given their opposite roles in physiological functions, confirmed by the modest effects of melatonin or MT<sub>1</sub>/MT<sub>2</sub> non-selective agonists when used in both preclinical and clinical studies as hypnotic drugs. In sum, MT<sub>1</sub> and MT<sub>2</sub> 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<sub>2</sub> agonists or partial agonists might be indicated for NREM-related sleep and/or anxiety disorders, the MT<sub>1</sub> agonists or partial agonists might be so for REM-related sleep disorders. Furthermore, MT<sub>1</sub> but not MT<sub>2</sub> receptors seem involved in the regulation of the circadian rhythm. Future research will help further develop MT<sub>1</sub> and/or MT<sub>2</sub> receptors as targets for neuropsychopharmacology drug development.</p>