Chronic Fluoxetine Treatment of Socially Isolated Rats Modulates Prefrontal Cortex Proteome

Fluoxetine (Flx) is the most commonly used antidepressant to treat major depressive disorder. How-ever, its molecular mechanisms of action are not defined as yet. A comparative proteomic approach was used to identify proteome changes in the prefrontal cortex (PFC) cytosolic and non-synaptic mitochondria (NSM)-enriched fractions of adult male Wistar rats following chronic social isolation (CSIS), a rat model of depression, and Flx treatment in CSIS and control rats, using liquid chromatography online tandem mass spectrometry. Flx reversed CSIS-induced depressive -like behavior according to preference for sucrose and immobility in the forced swim test, indicating its antidepressant effect. Flx treatment in controls led to an increase of the expression of cytosolic proteins involved in the microtubule cytoskeleton and intracellular calcium homeostasis and of enzymes involved in bioenergetic and transmembrane transport in NSM. CSIS downregulated the cytosolic pro-teins involved in proteasome pathway, and glutathione antioxidative system, and upregulated the expression of enzymes participating in mitochondrial-energy metabolism and transport. The presence of cytochrome c in the cytosol may suggest compromised mitochondrial membrane integrity. Flx treatment in CSIS rats downregulated protein involved in oxidative phosphorylation, such as complex III and manganese superoxide dismutase, and upregulated vesicle-mediated transport and synaptic signaling proteins in the cytosol, and neuronal calcium -binding protein 1 in NSM. Our study identified PFC modulated proteins and affected biochemical pathways that may represent potential markers/targets underlying CSIS-induced depression and effective Flx treatment, and highlights the role of protein systems involved in NSM and various metabolic pathways potentially involved in neuronal plasticity.(c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

Fluoxetine was found to reverse depressive behavior induced by chronic social isolation and alter the protein composition of cytosolic and non-synaptic mitochondria-enriched fractions in the prefrontal cortex of rats. It regulated proteins associated with mitochondrial energy metabolism and transport, cytoplasmic cytoskeleton, and calcium homeostasis, with a particular downregulation of proteins involved in oxidative phosphorylation in the depression model rats. These findings provide valuable insights into the mechanisms of action of antidepressant drugs.