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

Abstract

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.

Keywords: BDNF; Depression; Fluoxetine; Melatonin; TrkB.

Fig. 1

Schematic of the experimental design.

Fig. 2

Effects of sub-chronic restraint stress and drug treatment on body weight, fur state, and plasma corticosterone levels after an acute stress challenge. A All groups of mice had comparable body weight. B Progression of fur quality during the stress and drug treatment procedures. Combined fluoxetine and melatonin treatment improved the fur state in stressed mice. C Either fluoxetine or melatonin administration alone or combined treatment reduced the plasma corticosterone levels at 30 min after the forced swim test. ***P < 0.001 versus CTL. ^## P < 0.01, ^### P < 0.001 versus SRS. n = 7 mice per group.

Fig. 3

Sub-chronic restraint stress and drug treatment did not affect locomotor activity and anxiety-related behavior in the open field test. A–D All groups of mice were similar in the total distance traveled, time in the center zone, entries to the center zone, and number of rearings. n = 7 mice per group.

Fig. 4

Sub-chronic restraint stress and drug treatment did not affect spatial working memory in the Y-maze spontaneous alternation task. A–B All groups had comparable spontaneous alternation rates and number of arm entries. n = 7 mice per group.

Fig. 5

Combined fluoxetine and melatonin treatment reduced depression-like behavior. A–D Combined fluoxetine and melatonin treatment decreased the latency to groom and increased the number of grooming bouts in the splash test, and decreased immobility time but increased struggle time in the forced-swim test. ***P < 0.001 vs CTL; ^## P < 0.01, ^### P < 0.001 vs SRS; n = 7 mice per group.

Fig. 6

Combined fluoxetine and melatonin treatment normalized BDNF–TrkB signaling in the hippocampus (A–B), but not in the prefrontal cortex (C–D). *P < 0.05, **P < 0.01, ***P < 0.001 vs CTL; ^# P < 0.05, ^## P < 0.01 vs SRS group; n = 7 mice per group.