Corticosterone (CORT), the main HPA-axis glucocorticoid hormone in rodents, is involved in the regulation of animal stress responses. However, the neural mechanisms underlying the effects of corticosteroids on depression are yet to be elucidated. We found that fluoxetine reversed neurite growth inhibition induced by COAT in PC12 cells, a widely used model system for neurobiological and neurotoxicological studies. Transcriptome profiling showed that 1,609 genes were up-regulated, whereas 1,764 genes were down-regulated significantly in the CORT group in comparison with the Control group. Of them, the expression of 589 DEGs was reversed after fluoxetine treatment, and genes related to cell morphogenesis, neurite growth, and immune function were involved in the neuroprotective effect of fluoxetine against CORT. Furthermore, expression of neurite growth-related genes, such as such as Calpain 2 (Capn2), vesicle-associated membrane protein 7 (Vamp7) and C-type natriuretic peptide (Cnp), altered in a brain region- or treatment-specific manner in the animal models of depression. Therefore, the interaction between stress, glucocorticoids, and neurite growth inhibition may be a candidate pathophysiology underlying major depressive disorder (MDD), and the identification of Capn2, Vamp7 and Cop might provide insight into treatment of MDD.