Objective The present study is to explore the effect of the chronic multiplestress on learning and memory of rats and the role of cAMP/PKA-CREB pathway in its mechanism. Methods Adult male Wistar rats were randomly divided into 3 groups: the control rats were housed in normal situations without any treatment; the chronically single str essed rats were exposed to restraint stress 6 hours a day for 6 weeks; the chronically multiplestressed rats were irregularly and alternatively subjected to 4 stressors for 6 weeks. After the stress experiment, all rats were tested for spatial learning and memory in Morris water maze (MWM). The expression of PKA-CSUB>β/SUB> and pCREB in different subfields of the hippocampus was assayed by using immunohistochemistry and the level of BDNF and Bcl-2 mRNAs in hippocampal tissues was determined by RT-PCR. Results The latency to escape from water in MWM after stress, as compared with control (18.9+13.0)s, the latency to escape of the chronically multiplestressed (14.2+5.8)s was shorten significantly (P<0.05), indicating enhanced the spatial memory, while no apparent changes were observed in singlestressed (20.4+12.8)s (P>0.05). Compared with control, the expression of PKA-Cβ in hippocampal area CA1 and CA3 and the expression of pCREB in area CA1 and dentate gyrus (DG) were distinctively higher in multiplestressed rats (P<0.05), while no significant difference of the expression was discovered in singlestressed rats (P>0.05). No obvious difference was observed in the expression of hippocampal BDNF and Bcl-2 mRNAs among the 3 groups (P>0.05). Conclusion These results indicate that chronic mu