The wide-scale analysis of protein expression provides a powerful strategy for the molecular exploration of complex pathophysiological mechanisms, such as the response to antidepressants. Using a 2D proteomic approach we investigated the Flinders Sensitive Line (FSL), a genetically selected rat model of depression, and the control Flinders Resistant Line (FRL). To evaluate gene-environment interactions, FSL and FRL pups were separated from their mothers for 3 h (maternal separation, MS), as early-life trauma is considered an important antecedent of depression. All groups were treated with either escitalopram (Esc) admixed to food (25 mg/kg.d) or vehicle for 1 month. At the week 3, forced swim tests were performed. Protein extracts from prefrontal/frontal cortex and hippocampus were separated by 2D electrophoresis. Proteins displaying statistically significant differences in expression levels were identified by mass spectrometry. Immobility time values in the forced swim test were higher in FSL rats and reduced by antidepressant treatment. Moreover, the Esc-induced reduction in immobility time was not detected in MS rats. The impact of genetic background in response to Esc was specifically investigated here. Bioinformatics analyses highlighted gene ontology terms showing tighter associations with the modulated proteins. Esc modulated protein belonging to cytoskeleton organization in FSL; carbohydrate metabolism and intracellular transport in FRL. Proteins differently modulated in the two strains after MS and Esc play a role in cytoskeleton organization, vesicle-mediated transport, apoptosis regulation and macromolecule catabolism. These findings suggest pathways involved in neuronal remodelling as molecular correlates of response to antidepressants in a model of vulnerability.