Melatonin MT1 receptor as a novel target in neuropsychopharmacology: MT1 ligands, pathophysiological and therapeutic implications, and perspectives.

Abstract

Melatonin (MLT), a neuromodulator mainly acting through two G-protein coupled receptors MT1 and MT2, regulates many brain functions, including circadian rhythms, mood, pain and sleep. MLT and non-selective MT1/MT2 receptor agonists are clinically used in neuropsychiatric and/or sleep disorders. However, the selective roles of the MT1 and MT2 receptors need to be clarified. Here, we review the role of the MT1 receptor in neuropsychopharmacology, describe the anatomical localization of MT1 receptors in the brain, discuss the medicinal chemistry, biochemistry and molecular aspects of the receptor, and explore the findings linking MT1 receptors to psychiatric and neurological disorders. MT1 receptors are localized in brain regions which regulate circadian rhythms, sleep, and mood, such as the suprachiasmatic nucleus, cortex, hippocampus, dorsal raphe nucleus and lateral hypothalamus. Their activation modulates intracellular signaling pathways also targeted by psychoactive drugs, including antidepressants and mood stabilizers. MT1 receptor knockout mice display increased anxiety, a depressive-like phenotype, increased propensity to reward and addiction, and reduced Rapid-Eye-Movement sleep. These behavioral dysfunctions are associated with altered serotonergic and noradrenergic neurotransmissions. Several studies indicate that the MT1, rather than MT2, receptor is implicated in circadian rhythm regulation. The involvement of MT1 receptors in Alzheimer's and Huntington diseases has also been proposed. Postmortem studies in depressed patients have further confirmed the possible involvement of MT1 receptors in depression. Overall, there is substantial evidence indicating a role for MT1 receptor in modulating brain function and mood. Consequently, this MLT receptor subtype deserves to be further examined as a novel target for neuropsychopharmacological drug development.

• Authors: Stefano Comai, Martha Lopez-Canul, Danilo De Gregorio, Ada Posner, Mohamed Ettaoussi, Fabrizia Claudia Guarnieri, Gabriella Gobbi
• Journal: Pharmacological research (Pharmacol Res) Vol. 144 Pg. 343-356 (06 2019) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 31029764 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Ligands
• Receptor, Melatonin, MT1

Topics

• Animals
• Circadian Rhythm (drug effects)
• Drug Discovery
• Humans
• Ligands
• Molecular Targeted Therapy
• Mood Disorders (drug therapy, metabolism)
• Neurodegenerative Diseases (drug therapy, metabolism)
• Psychotic Disorders (drug therapy, metabolism)
• Receptor, Melatonin, MT1 (analysis, metabolism)
• Sleep Wake Disorders (drug therapy, metabolism)
• Substance-Related Disorders (drug therapy, metabolism)