Clinical and preclinical studies showed that aspirin may have the effect of emotion regulation, but the mechanisms underlying the antidepressant effect of aspirin remain unknown. In this study, we examined the effect of aspirin on depression-like behaviors and the neurochemical, endocrine and immune responses induced by acute forced swim test (FST) and chronic cold water swim (CCWS). Depression-like behaviors were detected by the despair behavior in FST, saccharin preference test and open field test. Anxiety-like behaviors were tested in elevated plus-maze (EPM). The high performance liquid chromatographic method was used to determine the level of monoamines and their metabolites in different brain areas. ELISA was used to determine the level of corticosterone and pro-inflammation cytokines in serum. The main results were as follows: Part One: The antidepressant effect of aspirin in FST and its mechanisms. Aspirin decreased immobility behavior and increased climbing behavior in FST depending on dosage. Aspirin increased the level of norepinephrine (NE) in hippocampus (HIP) and 5-hydroxyindole acetic acid (5-HIAA, the metabolite of serotonin) in most brain areas tested. In addition, aspirin had no effects on the metabolic rate of 5- hydroxytryptamine (5-HT) (5-HIAA/5-HT) in all tested brain regions except HIP. FST increased the release of corticosterone and pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in peripheral blood. Aspirin showed no significant effect on the increased corticosterone response in FST, but reversed the increase of IL-6 and TNF-α relying on dosage. These results suggested that aspirin might exert antidepressant effect in FST via increasing NEergic and 5-HTergic transmission, as well as inhibiting the release of pro-inflammatory factor. Part Two: The antidepressant effect of aspirin in CCWS and its mechanisms. Aspirin improved the lower saccharin preference index in stressed rats depending on dosage, and increased the horizontal distance traveled in open field. Aspirin in high dose reduced both the retention time and the number of entries in open arms in EPM in stressed rats, but not controls. These data demonstrated that aspirin can ameliorate the depression-like behaviors induced by CCWS, while may increase anxiety level of stressed rats in high dose. However, CCWS had no significant effects on the level of monoamines, corticosterone and pro-inflammatory cytokines (IL-6 and TNF-α). In addition, there was no obvious dose-response relationship between aspirin doses and the level of monoamines, corticosterone and pro-inflammatory cytokines in stressed rats. In summary, aspirin can ameliorate the depression-like behaviors induced both by FST and CCWS. But the brain monoamines and the pro-inflammatory cytokines might be involved in the antidepressant effect of aspirin in FST, while their roles in depression-like behaviors induced by CCWS remain unknow, as they were not significantly affected by CCWS.