Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study.

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD. Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

Citation

Margherita Tassan Mazzocco, Claudia Pisanu, Luigi Russo, Clementina Acconcia, Marco Cambiaghi, Sofia De Girolamo, Alessio Squassina, Laura Cherchi, Elena Monzani, Francesca Scebba, Debora Angeloni, Danilo De Gregorio, Sofia Nasini, Stefano Dall'Acqua, Stefania Sut, Federico Suprani, Mario Garzilli, Beatrice Guiso, Vittoria Pulcinelli, Maria Novella Iaselli, Ilaria Pinna, Giulia Somaini, Laura Arru, Carolina Corrias, Pasquale Paribello, Federica Pinna, Gabriella Gobbi, Flavia Valtorta, Bernardo Carpiniello, Mirko Manchia, Stefano Comai. Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study. Pharmacological research. 2023 Dec;198:106993

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PMID: 37972722

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