Hippocampal energy metabolism reprogramming underlies individual differences in paroxetine-facilitated contextual...

Individual variability in response to selective serotonin reuptake inhibitors (SSRIs) remains a major challenge in the treatment of anxiety-related disorders. Impaired fear extinction is a core feature of stress-related psychopathologies. Although chronic SSRI administration has been shown to enhance fear extinction, the biological basis underlying differential treatment responsiveness is poorly understood. In the present study, we examined hippocampal molecular alterations associated with divergent behavioral responses to chronic paroxetine treatment in a contextual fear extinction paradigm. Based on freezing behavior during the extinction retention test, paroxetine-treated rats were stratified into high- and low-response subgroups. Data-independent acquisition-based proteomics revealed pronounced alterations in pathways related to synaptic function, mitochondrial processes, and metabolic regulation in the hippocampus of paroxetine high responders. Subsequent targeted metabolite quantification further implicated multiple energy-related pathways, including the pentose phosphate pathway, purine metabolism, and the tricarboxylic acid cycle, as metabolic features associated with divergent contextual fear extinction phenotypes, accompanied by altered levels of pathway-specific metabolites. These results suggest that adaptive hippocampal energy metabolism reprogramming may support divergent fear extinction phenotypes following chronic paroxetine treatment, providing mechanistic insight into differential treatment effects in fear-related disorders.