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AIM: To investigate changes in vasoactive intestinal polypeptide (VIP) and corticotrophinreleasing factor (CRF) in the plasma and duodenum of chronic stressinduced depressed rats and the effects of fluoxetine hydrochloride (fluoxetine) treatment on depressioninduced changes in VIP and CRF.METHODS: A Sprague-Dawley rat model of chronic stress-induced depression was produced. Thirty experimental rats were randomly divided into the following groups: control group, saline-treated depressed group, and fluoxetine-treated depressed group. Openfield testing was performed to assess the rats' behavior.VIP and CRF levels in plasma were measured by ELISA.Immunofluorescence techniques combined with laser scanning confocal microscopy (LSCM) were used to investigate VIP and CRF expression in the duodenum.RESULTS: The open-field behavior, both crossing and rearing, of depression model rats, decreased significantly compared with those of normal control rats over 5 min.Defecation times increased significantly. Compared to the control group, FITC fluorescence of duodenal CRF expression and plasma CRF levels in the depressed rats increased significantly (fluorescence intensity of duodenal CRF: 11.82 ± 2.54 vs 25.17 ± 4.63; plasma CRF: 11.82 ± 2.54 ng/L vs 25.17 ± 4.63 ng/L, P＜0.01),whereas duodenal VIP expression and plasma VIP levels decreased significantly (fluorescence intensity of duodenal VIP: 67.37 ± 18.90 vs 44.51 ± 16.37; plasma VIP: 67.37 ± 18.90 ng/L vs 44.51±16.37 ng/L, P ＜ 0.01).Fluoxetine improved depressed behavior, increased VIP expression and decreased CRF expression in plasma and the duodenal tissue of depressed rats.CONCLUSION: Chronic stress can induce injury to the duodenum, accompanied by increasing CRF and decreasing VIP in the plasma and duodenum. Treatment with fluoxetine can ameliorate pathological changes in the duodenum of depressed rats, which suggests that antidepressants are an effective therapeutic agent for some duodenal diseases caused by chronic stress. VIP is a potential therapeutic strategy.