Social and environmental stress is a risk factor for mental illnesses. Therefore, the molecular bases of stress‐induced behavioral changes have been studied using various rodent stress model. Authors examined the molecular changes which are induced in the medial prefrontal cortex (mPFC) by acute and chronic stress and their behavioral consequences. Acute stress activates mesocortical dopaminergic pathway and dopamine D1 receptor located in excitatory neurons in mPFC, which suppressed the induction of social avoidance through. Chronic stress suppressed mesocortical dopaminergic pathway via COX‐1‐PGE₂‐EP1, which induces social avoidance. Additionally, chronic stress activates mPFC microglia via Toll‐like receptor 2 and 4, and activated microglia releases proinflammatory cytokines, namely IL‐1α and TNFα, which induces social avoidance. These results revealed that chronic stress induces neuroinflammation which is derived from microglia, leading to stress‐induced behavioral changes. Authors have no potential conflicts of interest to be disclosed.