Exposure to stress is thought to play an important role in the etiology of depression. Dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis characterized by glucocorticoid negative feedback resistance is frequently observed in human depressives. Additionally, dysfunctions of the dopaminergic and serotonergic systems in the prefrontal cortex (PFC) are thought to be involved in the development of a depressive state. In rats, chronic stress induces a behaviorally depressive state, concomitant with dysregulation of the HPA axis and reductions in dopaminergic and serotonergic transmissions in the PFC. Considering that dysregulation of the HPA axis is associated with relapse and persistency of depression, it is possible that the chronic stress-induced depressive state persists during long-term rest after its exposure. In the present study, we examined this possibility in rats and found that the behaviorally depressive state in the rotarod test, negative feedback resistance in the dexamethasone suppression test, and a decrease in the extracellular concentration of dopamine but not serotonin in the PFC persisted for 3 months following a 4-week stress session. These results suggest that dysregulation of the HPA system and reduced dopaminergic transmission in the PFC underlies persistent behavioral depression following chronic stress.