Pharmacological Research (Dec 2023)
Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study
- 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
Affiliations
- Margherita Tassan Mazzocco
- IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita Salute San Raffaele University, Milan, Italy
- Claudia Pisanu
- Department of Biomedical Science, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Cagliari, Italy
- Luigi Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania ''L. Vanvitelli'', Caserta, Italy
- Clementina Acconcia
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania ''L. Vanvitelli'', Caserta, Italy
- Marco Cambiaghi
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
- Sofia De Girolamo
- IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita Salute San Raffaele University, Milan, Italy
- Alessio Squassina
- Department of Biomedical Science, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Cagliari, Italy
- Laura Cherchi
- IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita Salute San Raffaele University, Milan, Italy
- Elena Monzani
- IRCCS San Raffaele Scientific Institute, Milan, Italy
- Francesca Scebba
- Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, Via G. Moruzzi, 56124 Pisa, Italy
- Debora Angeloni
- Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, Via G. Moruzzi, 56124 Pisa, Italy; The Institute of Biorobotics, Scuola Superiore Sant’Anna, Via G. Moruzzi, 56124 Pisa, Italy
- Danilo De Gregorio
- IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita Salute San Raffaele University, Milan, Italy
- Sofia Nasini
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
- Stefano Dall’Acqua
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
- Stefania Sut
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
- Federico Suprani
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Mario Garzilli
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Beatrice Guiso
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Vittoria Pulcinelli
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Maria Novella Iaselli
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Ilaria Pinna
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Giulia Somaini
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Laura Arru
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Carolina Corrias
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Pasquale Paribello
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Federica Pinna
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Gabriella Gobbi
- Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada
- Flavia Valtorta
- IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita Salute San Raffaele University, Milan, Italy
- Bernardo Carpiniello
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy
- Mirko Manchia
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada; Corresponding author at: Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
- Stefano Comai
- IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy; Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada; Department of Biomedical Sciences, University of Padua, Padua, Italy; Corresponding author at: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
- Journal volume & issue
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Vol. 198
p. 106993
Abstract
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.
