Prefrontal Cortex Molecular Signatures of Chronically Socially Isolated Rats and Their Response to Fluoxetine Treatment

Despite intensive scientific and clinical research, the pathophysiological mechanisms of major depressive disorder (MDD) are still not fully understood, impeding the discovery of new effective treatments. A significant clinical challenge is the delayed onset of antidepressant efficacy, which limits timely therapeutic intervention. Recent advances in proteomics and metabolomics offer new opportunities to explore these complexities at the molecular level. This review presents a comprehensive analysis of the biochemical alterations and affected molecular pathways associated with depressive-like behavior in adult male rats subjected to chronic social isolation stress (CSIS), a well-established rodent model of depression. Additionally, it examines the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) commonly used in MDD treatment, to uncover potential mechanisms underlying the drug's therapeutic action. By integrating mass spectrometry-based proteomic and metabolomic analyses of cytosolic, nonsynaptic mitochondrial, and synaptosomal-enriched fractions of the rat prefrontal cortex, an area crucially implicated in both clinical and animal models of depression, this review provides insights into state-specific molecular signatures. The findings discussed here contribute to a deeper understanding of the neurobiological basis of depression and offer novel insights into the biochemical mechanisms mediating antidepressant effects, with potential for the development of improved therapeutic strategies.