Glutamatergic processes are strongly implicated in the pathophysiology and treatment of depression, including the antidepressant effects of N-methyl-D-aspartate (NMDA) receptor antagonists. This study was designed to see whether memantine, a noncompetitive NMDA antagonist, has antidepressant effects in behaviors and synaptic plasticity. Rats were randomly divided into control, stressed, and stressed+memantine groups. The animal model was established by chronic unpredictable stress. Memantine (20 mg/kg) was administrated i.p. for 21 days. Weight, sucrose consumption, water maze behavior and prefrontal cortical long-term potentiation (LTP) were measured, followed by immunohisotchemistry test of NR2B expression. Results showed that rats' weight and sucrose consumption were significantly lower in stressed group than those in control group, while the last time of sucrose consumption was improved by memantine. Rats in stressed group performed worse in reversal learning related stages, while rats in stressed+memantine group performed worse in spatial memory related stages. LTP test showed lower amplitude of field excitatory postsynaptic potential in prefrontal cortex in stressed group. Immunohistochemistry showed lower expression of NR2B receptor in prefrontal cortex in stressed group, and higher expression in hippocampus in stressed+memantine group. In conclusion, memantine in dose of 20 mg/kg improves the sucrose consumption, reversal learning and prefrontal cortical synaptic plasticity, but impairs spatial memory, which is probably due to different extent of up-regulating NR2B receptor expression in prefrontal cortex and hippocampus in stressed rats.