The etiology of depression is still unclear, but multiple studies explained several theories attempting to describe the development of depression. Depressive symptoms are usually combined with morphological and neuroendocrine deficits in the mesolimbic system including hippocampus. One drug or combination of more than one are associated with high rate of non-response, partial, or delayed response onset from weeks to months. Thus, the need for new and better treatment is mandatory. Purpose of the study; to assess the mechanisms and effects of a single dose of ketamine injection in experimental model of chronic unpredictable mild stress (CUMS). Basic procedures; thirty rats were separated into 3 groups: control (C), CUMS group in which rats faced different physical stressors for six weeks, Ketamine treated CUMS group in which rats faced different physical stressors for six weeks then every rat received a single sub-anesthetic intraperitoneal injection (i.p) of ketamine at a dose of 10 mg/kg, 24 hours prior to the end of the experiment. After the end of the CUMS period, before and after ketamine administration, behavioral test was executed as sucrose preference test. In addition, serotonin concentration was measured in hippocampus of the dissected rat brain. Main findings: the administration of single i.p injection of ketamine significantly increased sucrose preference test and hippocampal serotonin level as compared to CUMS group but still significantly lower than the control group. Principle conclusion: Chronic stress exposure induced many brain damaging events and the administration of ketamine ameliorating the depressive symptoms.