Major Depressive Disorder (MDD) poses a global burden, affecting over 300 million individuals and presenting a significant therapeutic challenge due to the limited efficacy of conventional antidepressants. The investigation of rapid-acting antidepressants, exemplified by ketamine, has garnered attention, yet the intricate underlying processes remain incompletely understood.This study systematically evaluated the acute effects of ketamine (10 mg/kg, i.p.) and fluoxetine (3 x 10 mg/kg, i.p.) on depression-like behavior in animal models subjected to chronic restraint stress (CRS, 6 weeks) and chronic corticosterone administration in drinking water (CORT, 6 weeks).Compared to unstressed animals, CRS induced an increase in immobility time in the forced swim test (FST) and latency to eat in the novelty-suppressed feeding test (NSFT), without altering sucrose consumption. Additionally, CRS prompted an anxiogenic response, evidenced through decreased time spent in the center of an open field.Similarly, CORT led to increased immobility time in the FST and latency to eat in the NSFT, accompanied by reduced sucrose consumption in the sucrose preference test (SPT). An anxiogenic response in the open field was also induced by CORT.Interestingly, ketamine, but not fluoxetine, ameliorated the CORT-induced effects in the FST. However, both ketamine and fluoxetine failed to alleviate anhedonia and anxiety provoked by CORT administration.In conclusion, discernible distinctions emerged in the behavioral effects between animal models and responses to ketamine versus fluoxetine, enhancing our understanding of the nuanced actions of rapid-acting antidepressants.