Abstract: Objective To investigate the effect of fluoxetine on the expression of fibroblast growth factor-2, fibroblast growth factor receptor 1 and 5-hydroxytryptamine (5-HT) 1 A receptor in the hippocampus of depression model rats. Methods The behavior scores was evaluated by using open-field test. Forty healthy male SD rats weighting 210 to 290 g with the similar score were selected and randomly divided into 4 groups (8 in each group) based on the random number table, including chronic unpredictable mild stress (CUMS) group, CUMS plus fluoxetine group, control group and fluoxetine group. Chronic mild unpredicted stress was taken to establish rat depression mode1 for 21 days. The fluoxetine group and CUMS plus fluoxetine group were treated with intragastric administration of fluoxetine[5 mg/(kg·d)], meanwhile the control group and CUMS group were treated with 0.5% carboxymethyl cellulose sodium in the same way. The openfield test and sucrose consumption were used to evaluate the depression behaviors of rats. And the expression of FGF-2, FGFR1 and 5-HT1 AR in the hippocampus of rats were detected by western blot. Results ① The open-field test and sucrose consumption showed that the rat model of depression has been established successfully. Compared with the CUMS group, the sucrose consumption, crossing score and rearing score in the CUMS plus fluoxetine group were significantly increased, while the number of defecate was significantly decreased (all P<0.05). ② Compared with control group, the level of FGF-2, FGFR1 and 5-HT1 AR in hippocampus of rats were significantly decreased in CUMS group (P<0.05), while fluoxetine group showed no significant difference (P>0.05). The expression of FGF-2, FGFR1 and 5-HT1 AR in hippocampus of the CUMS plus fluoxetine group were significantly higher than the CUMS group (all P<0.05). Conclusion Fluoxetine can be used to improve depressive behaviors, which maybe associate with the increased expression level of FGF-2, FGFR1 and 5-HT1 AR protein in rat hippocampus.