IRCCS San Raffaele Scientific Institute, Milan, Italy; School of Medicine, Vita Salute San Raffaele University, Milan, Italy.
Department of Biomedical Science, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Cagliari, Italy.
Pharmacol Res. 2023 Dec;198:106993. doi: 10.1016/j.phrs.2023.106993. Epub 2023 Nov 14.
The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT and MT, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT 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 MT 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 MT 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 MT receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT rs2165666 variant. Overall, this work lends support to the potentiality of MT receptors as target for the treatment of BD.
双相情感障碍 (BD) 的治疗仍然是一个挑战。褪黑素 (MLT) 通过其两个受体 MT 和 MT 发挥作用，在调节昼夜节律方面发挥着关键作用，而昼夜节律在 BD 中是失调的。我们采用转化方法，研究了 MT 受体在 BD 的病理生理学和精神药理学中的意义和潜力。我们使用双相情感障碍躁狂期的小鼠模型（Clock 突变体（ClockΔ19）小鼠）来研究 UCM871（一种选择性部分激动剂）对 MT 受体的激活作用，在行为药理学测试和体内电生理学中进行研究。然后，我们在分离的膜上进行了高分辨率核磁共振研究，以表征 UCM871 的相互作用的分子机制。最后，在一组 BD 患者中，我们研究了 BD 的临床测量与位于 MT 受体和 CLOCK 基因中的遗传变异之间的联系。我们证明了：1）UCM871 可以逆转 ClockΔ19 小鼠的行为和电生理异常；2）UCM871 促进 MT 受体的激活状态；3）MT rs2165666 变体的遗传配置取决于 MLT 水平，与严重躁狂发作次数之间存在显著关联。总的来说，这项工作为 MT 受体作为 BD 治疗靶点的潜力提供了支持。
