Melatonin Augments the Effects of Fluoxetine on Depression-Like Behavior and Hippocampal BDNF-TrkB Signaling
Melatonin Augments the Effects of Fluoxetine on Depression-Like Behavior and Hippocampal BDNF-TrkB Signaling
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褪黑素增强氟西汀对抑郁样行为和海马 BDNF-TrkB 信号传导的影响
DOI：
10.1007/s12264-017-0189-z
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发表时间：
2018-04-01
影响因子：
5.6
通讯作者：
Wang, Xiao-Dong
中科院分区：
文献类型：
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作者：
Li, Kun;Shen, Si;Wang, Xiao-Dong
抑郁症是一种衰弱的精神疾病，具有巨大的社会经济负担，其治疗依赖于抗抑郁药物，包括选择性5-羟色胺再摄取抑制剂(SSRIs)。近年来，与5-羟色胺能系统密切相关的黑素能系统被认为与抑郁症的病理生理和治疗密切相关。然而，目前尚不清楚SSRI和褪黑素联合治疗是否具有协同抗抑郁作用。在这项研究中，我们应用了亚慢性束缚应激范式，并评估了氟西汀和褪黑素联合应用对成年雄性小鼠的潜在抗抑郁作用。亚慢性束缚应激(每天6h，持续10d)可引起抑郁样行为，表现为皮毛状态恶化，飞溅试验中的梳毛潜伏期延长，强迫游泳试验中的不动时间延长。在压力暴露期间重复服用10毫克/公斤的氟西汀或褪黑素都不能防止抑郁症的表型。然而，选择剂量的氟西汀和褪黑素联合治疗可以减轻应激诱导的行为异常。此外，我们发现联合治疗的抗抑郁作用与脑源性神经营养因子(BDNF)-原肌球蛋白受体激酶B(TrkB)信号在海马区的正常化有关，而与前额叶皮质的信号正常化无关。我们的研究结果表明，氟西汀和褪黑素联合治疗可能通过恢复海马区BDNF-TrkB信号而发挥协同抗抑郁作用。
Depression is a debilitating psychiatric disorder with a huge socioeconomic burden, and its treatment relies on antidepressants including selective serotonin reuptake inhibitors (SSRIs). Recently, the melatonergic system that is closely associated with the serotonergic system has been implicated in the pathophysiology and treatment of depression. However, it remains unknown whether combined treatment with SSRI and melatonin has synergistic antidepressant effects. In this study, we applied a sub-chronic restraint stress paradigm, and evaluated the potential antidepressant effects of combined fluoxetine and melatonin in adult male mice. Sub-chronic restraint stress (6 h/day for 10 days) induced depression-like behavior as shown by deteriorated fur state, increased latency to groom in the splash test, and increased immobility time in the forced-swim test. Repeated administration of either fluoxetine or melatonin at 10 mg/kg during stress exposure failed to prevent depression-like phenotypes. However, combined treatment with fluoxetine and melatonin at the selected dose attenuated stress-induced behavioral abnormalities. Moreover, we found that the antidepressant effects of combined treatment were associated with the normalization of brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the hippocampus, but not in the prefrontal cortex. Our findings suggest that combined fluoxetine and melatonin treatment exerts synergistic antidepressant effects possibly by restoring hippocampal BDNF-TrkB signaling.