ObjectiveTo investigate the change of phosphorylated p44/42 extracellular signalregulated kinase (pERK1/2) and c-fos expression induced by singleprolonged stress (SPS) in medial prefrontal cortex (mPFC). Methods Forty-five male Wistar rats were divided into control group, SPS group and PD98059-SPS group. The rats of SPS group and PD98059-SPS group were exposed to single-prolonged stress (SPS), and that of PD98059-SPS group were bilaterally infused the PD98059, inhibitor of ERK, into the mPFC. The behavior was examined using openfield test, elevated plusmaze and Morris water maze. The expression of pERK1/2 in mPFC was detected with immunohistochemical staining and Western blotting. And reverse transcription-polymerase chain reaction (RT-PCR) was employed to detect the c-fos mRNA. ResultsSPS exposure resulted in pronounced anxiety-like behavior and learning and spatial memory impairments. PD98059 significantly ameliorated the behavior alteration. Absorbance of pERK1/2 positive cell, expression of pERK1/2 and expression of c-fos mRNA of SPS rats were 51.54±5.41, 89.61±3.25 and 0.91±0.13 respectively, while the control group rats were 12.18±1.61, 34.22±5.83 and 0.13±0.03, and PD98059-SPS group rats were 26.26±1.42, 60.59±5.88 and 0.35±0.11. These data suggest that expressions of pERK1/2 and c-fos mRNA in mPFC increased significantly after rats were exposed to SPS (EM>P/EM><