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.

Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study / Tassan Mazzocco, M.; Pisanu, C.; Russo, L.; Acconcia, C.; Cambiaghi, M.; De Girolamo, S.; Squassina, A.; Cherchi, L.; Monzani, E.; Scebba, F.; Angeloni, D.; De Gregorio, D.; Nasini, S.; Dall'Acqua, S.; Sut, S.; Suprani, F.; Garzilli, M.; Guiso, B.; Pulcinelli, V.; Iaselli, M. N.; Pinna, I.; Somaini, G.; Arru, L.; Corrias, C.; Paribello, P.; Pinna, F.; Gobbi, G.; Valtorta, F.; Carpiniello, B.; Manchia, M.; Comai, S.. - In: PHARMACOLOGICAL RESEARCH. - ISSN 1043-6618. - 198:(2023). [10.1016/j.phrs.2023.106993]

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

De Gregorio D.;Valtorta F.;Comai S.
Ultimo
2023-01-01

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.
2023
Bipolar disorder
Clock gene
Melatonin
MT
1
receptor
Nuclear Magnetic Resonance
UCM871
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S1043661823003493-main.pdf

accesso aperto

Tipologia: PDF editoriale (versione pubblicata dall'editore)
Licenza: Creative commons
Dimensione 6.41 MB
Formato Adobe PDF
6.41 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/164416
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 1
social impact