Repeated fluoxetine treatment induces long-lasting neurotrophic changes in the medial prefrontal cortex of adult rats

Fluoxetine (Flx), a selective serotonin reuptake inhibitor, is extensively used to treat mood and anxiety disorders. Previous animal studies have shown that early-life exposure to Flx results in long-lasting behavioral alterations and neuroplasticity in the hippocampus and cortex, which may persist into adulthood. It remains unclear whether repeated Flx treatment in normal adult animals can induce lasting neuroplasticity and behavioral alterations persisting long beyond the treatment period. In this study, young adult rats (about 9 weeks old) were treated with Flx (10 mg/kg body weight, twice daily) for 15 consecutive days, and the effects of Flx on medial prefrontal cortex (mPFC) neuroplasticity and mPFC-related behaviors were assessed 20 days after the last injection. It was observed that the mPFC of Flx-treated rats had significant increases in the number of 5-bromodeoxyuridine-positive (BrdU+) cells, dendritic complexity/spine density in layer II/III pyramidal neurons, and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) expression levels, as well as a significant decrease in the number of parvalbumin-positive (PV+) interneurons. The Flx-treated rats exhibited higher motivation to explore new environments, evidenced by a significantly increased number of entries into the novel arm in the Y-maze test. However, they did not show any significant changes in the anhedonia and anxiety levels measured by sucrose preference and elevated plus maze tests respectively. In conclusion, repeated Flx treatment, with the paradigm used, induces long-lasting neuroplastic changes in the mPFC of normal adult rats; such changes and related behavioral manifestations may persist up to 20 days after the last dose.