Therapeutic treatment with fluoxetine using the chronic unpredictable stress model induces changes in neurotransmitters and circulating miRNAs in extracellular vesicles
M. Maetzi Estévez-Cabrera,
Fausto Sánchez-Muñoz,
Gilberto Pérez-Sánchez,
Lenin Pavón,
Adrian Hernández-Díazcouder,
J. Luis Córtes Altamirano,
C. Soria-Fregoso,
Alfonso Alfaro-Rodríguez,
Herlinda Bonilla-Jaime
Affiliations
M. Maetzi Estévez-Cabrera
Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, UAM, Av. San Rafael Atlixco 186, Leyes de Reforma, C.P. 09340, Ciudad de México, Mexico
Fausto Sánchez-Muñoz
Departamento de Inmunología, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1. Col. Belisario Domínguez - Sección XVI, Tlalpan, Ciudad de México, C.P. 14080, Mexico
Gilberto Pérez-Sánchez
Laboratorio de Psicoinmunología, Dirección de Investigaciones en Neurociencias del Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370, Ciudad de México, Mexico
Lenin Pavón
Laboratorio de Psicoinmunología, Dirección de Investigaciones en Neurociencias del Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370, Ciudad de México, Mexico
Adrian Hernández-Díazcouder
Posgrado en Biologia Experimental, Universidad Autónoma Metropolitana-Iztapalapa, UAM-I, Av. San Rafael Atlixco 186, Leyes de Reforma, C.P. 09340, Ciudad de México, Mexico
J. Luis Córtes Altamirano
Departamento de Neurociencias Basicas, Instituto Nacional de Rehabilitación, “Luis Guillermo Ibarra”. Calzada México Xochimilco No. 289, Col. Arenal de Guadalupe, C.P.14389, Ciudad de México, Mexico; Departamento de Quiropráctica, Universidad Estatal del Valle de Ecatepec, Ecatepec de Morelos, Estado de México, Mexico
C. Soria-Fregoso
Laboratorio de Ciencias Biomédicas/Área de Histología y Psicobiología, Departamento de Ciencias de la Tierra y de la Vida, Centro Universitario de los Lagos, Universidad de Guadalajara, Lagos de Moreno, 47460, Jalisco, Mexico
Alfonso Alfaro-Rodríguez
Departamento de Neurociencias Basicas, Instituto Nacional de Rehabilitación, “Luis Guillermo Ibarra”. Calzada México Xochimilco No. 289, Col. Arenal de Guadalupe, C.P.14389, Ciudad de México, Mexico
Herlinda Bonilla-Jaime
Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa, UAM-I, Av. San Rafael Atlixco 186, Leyes de Reforma, 09340, Ciudad de México, Mexico; Corresponding author.
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.
