title: Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: effects on energy metabolism.
abstract: Antidepressants affect glucocorticoid receptor (GR) functioning partly through modulation of its phosphorylation but their effects on mitochondrial GR have remained undefined. We investigated the ability of chronic fluoxetine treatment to affect chronic stress-induced changes of mitochondrial GR and its phosphoisoforms (pGRs) in the prefrontal cortex and hippocampus of female and male rats. Since mitochondrial GR regulates oxidative phosphorylation, expression of mitochondrial-encoded subunits of cytochrome (cyt) c oxidase and its activity were also investigated. Chronic stress caused accumulation of the GR in mitochondria of female prefrontal cortex, while the changes in the hippocampus were sex-specific at the levels of pGRs. Expression of mitochondrial COXs genes corresponded to chronic stress-modulated mitochondrial GR in both tissues of both genders and to cyt c oxidase activity in females. Moreover, the metabolic parameters in stressed animals were affected by fluoxetine therapy only in the hippocampus. Namely, fluoxetine effects on mitochondrial COXs and cyt c oxidase activity in the hippocampus seem to be conveyed through pGR232 in females, while in males this likely occurs through other mechanisms. In summary, sex-specific regulation of cyt c oxidase by the stress and antidepressant treatment and its differential convergence with mitochondrial GR signaling in the prefrontal cortex and hippocampus could contribute to clarification of sex-dependent vulnerability to stress-related disorders and sex-specific clinical impact of antidepressants.
authors: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia. Electronic address: miraz@vinca.rs.
authors: Miroslav
authors: M
authors: Adzic
authors: Iva
authors: I
authors: Lukic
authors: Milos
authors: M
authors: Mitic
authors: Jelena
authors: J
authors: Djordjevic
authors: Ivana
authors: I
authors: Elaković
authors: Ana
authors: A
authors: Djordjevic
authors: Marija
authors: M
authors: Krstic-Demonacos
authors: Gordana
authors: G
authors: Matić
authors: Marija
authors: M
authors: Radojcic
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D015153:Blotting, Western; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D030762:Estrous Cycle / Q000502:physiology; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D018687:Antidepressive Agents, Second-Generation; D011965:Receptors, Glucocorticoid; D005473:Fluoxetine; D012313:RNA; D003576:Electron Transport Complex IV
keywords: Chronic stress; Fluoxetine; Gender; Glucocorticoid receptor phosphorylation; Hippocampus; Mitochondria; Prefrontal cortex