Neuroscience Bulletin

, Volume 34, Issue 2, pp 303–311 | Cite as

Melatonin Augments the Effects of Fluoxetine on Depression-Like Behavior and Hippocampal BDNF–TrkB Signaling

  • Kun Li
  • Si Shen
  • Yu-Tian Ji
  • Xu-Yun Li
  • Li-San Zhang
  • Xiao-Dong Wang
Original Article


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.


Melatonin Fluoxetine Depression BDNF TrkB 



We thank the Core Facilities of Zhejiang University Institute of Neuroscience for technical assistance. This work was supported by the National Natural Science Foundation of China (81471369) and Innovative Experiments on Physiology of Zhejiang University School of Medicine. The authors have no conflicting financial interests.


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Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Kun Li
    • 1
  • Si Shen
    • 2
  • Yu-Tian Ji
    • 2
  • Xu-Yun Li
    • 3
  • Li-San Zhang
    • 4
  • Xiao-Dong Wang
    • 1
  1. 1.Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of NeurobiologyZhejiang University School of MedicineHangzhouChina
  2. 2.Zhejiang University School of MedicineHangzhouChina
  3. 3.Experimental Teaching Center of Basic MedicineZhejiang University School of MedicineHangzhouChina
  4. 4.Department of Neurology, Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina

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