Augmenting evidences disclose that stressful events evoke molecular alteration in brain, considered as a pathology in major depressive disorder (MDD). Chronic unpredictable mild stress (CUMS) induced hyperactivity in novel environment, decrease of social interaction time in social interaction test, prolongation of feeding latency in novelty suppressed feeding test, and enhancement of immobility in forced swimming test. The contents of dopamine and its metabolites, Dopamine (DA) turnover and protein level of tyrosine hydroxylase (TH) were increased by CUMS in the nucleus accumbens. The contents of serotonin, and protein levels of tryptophan hydroxylase (TPH) and TH were decreased by CUMS in the hippocampus and prefrontal cortex. Accompanies with activation of dopaminergic function, phosphorylation levels of ERK, Akt, and CREB were increased by CUMS in the nucleus accumbens. Administration of fluoxetine and aripiprazole during CUMS prevented the abnormal behavioral changes. These data suggest that CUMS induced depressive behaviors are associated with dopaminergic hyperfunction and ERK/Akt/CREB pathway in the nuclues accumbens, and serotonergic hypofunction in the prefrontal cortex and hippocampus.