Therapeutic treatment with fluoxetine using the chronic unpredictable stress model induces changes in neurotransmitters and circulating miRNAs in extracellular vesicles

The most widely prescribed antidepressant, fluoxetine (FLX), is known for its antioxidant and anti-inflammatory effects when administered post-stress. Few studies have evaluated the effects of FLX treatment when chronic stress has induced deleterious effects in patients. Our objective was to evaluate FLX treatment (20 mg/kg/day, i.v.) once these effects are manifested, and the drug's relation to extracellular circulating microRNAs associated with inflammation, a hedonic response (sucrose intake), the forced swim test (FST), and corticosterone levels (CORT) and monoamine concentrations in limbic areas. A group of Wistar rats was divided into groups: Control; FLX; CUMS (for six weeks of exposure to chronic, unpredictable mild stress); and CUMS + FLX, a mixed group. After CUMS, the rats performed the FST, and serum levels of CORT and six microRNAs (miR-16, -21, -144, -155, -146a, -223) were analyzed, as were levels of dopamine, noradrenaline, and serotonin in the prefrontal cortex, hippocampus, and hypothalamus. CUMS reduced body weight, sucrose intake, and hippocampal noradrenaline levels, but increased CORT, immobility behavior on the FST, dopamine concentrations in the prefrontal cortex, and all miRNAs except miR-146a expression. Administering FLX during CUMS reduced CORT levels and immobility behavior on the FST and increased the expression of miR-16, -21, -146a, -223, and dopamine. FLX protects against the deleterious effects of stress by reducing CORT and has an antidepressant effect on the FST, with minimally-modified neurotransmitter levels. FLX increased the expression of miRNAs as part of the antidepressant effect. It also regulates both neuroinflammation and serotoninergic neurotransmission through miRNAs, such as the miR-16. •CUMS reduced body weight, sucrose preference test, and hippocampal NA levels; increased CORT levels, the immobility behavior in the FST, and DA concentration in the prefrontal cortex.•CUMS reduced the miR-155, miR-21, miR-16, miR-223, miR-144.•FLX administration in CUMS reduced CORT levels and immobility behavior in the FST, and increased the miR-146a, miR-21,miR-16 and miR-223 but is not able to restore SPT and alterations in neurotransmitter levels.•FLX at this dose, time and stress phase has an antidepressant effect through different mechanisms, including the regulation of MIRNAs such as miR-16.