Effect of sub-optimal doses of fluoxetine plus estradiol on antidepressant-like behavior and hippocampal neurogenesis in ovariectomized rats

• FLX plus E2 at sub-threshold doses synergize to reduce immobility in the FST.
• FLX plus E2 synergize to stimulate hippocampal neurogenesis.
• FLX plus E2 promote dendrite complexity of doublecortin+ immature neurons.

SummaryEstrogens and antidepressants synergize to reduce depressive symptoms and stimulate neurogenesis and neuroplastic events. The aim of this study was to explore whether the antidepressant-like effect induced by the combination of low doses of estradiol (E2) and fluoxetine (FLX) involves changes in cell proliferation, early survival, morphology and dendrite complexity of hippocampal new-immature neurons.The antidepressant-like effects of E2 and/or FLX were evaluated by the forced swimming test (FST), cell proliferation was determined with the endogenous marker Ki67, survival of newborn cells was established with bromo-deoxiuridine (BrdU) and immature neurons were ascertained by doublecortin (DCX) labeling while their dendrite complexity was evaluated with Sholl analysis. Ovariectomized Wistar rats were randomly assigned to one of the following groups: Vehicle (saline/14 days + Oil/−8 h before FST); E2 (saline/14 days + E2 2.5 or 10 μg/rat; −8 h before FST); FLX (1.25 or 10 mg/kg for 14 days + oil −8 h before FST), and FLX plus E2 (FLX 1.25 mg/kg for 14 days + E2 2.5 μg/rat −8 h before FST).The combination of sub-threshold doses of FLX plus E2 produced antidepressant-like actions similar to those induced by FLX or E2 given independently at optimal doses. Only FLX at an optimal dose and the combination of FLX plus E2 increased cell proliferation, the number of DCX-labeled immature neurons and the complexity of their dendritic tree, suggesting that these events may be responsible for their antidepressant-like effect.