Objective:To explore the effects of electroacupuncture(EA)on rats with chronic unpredictable mild stress(CUMS)-induced depression and proteins related to endoplasmic reticulum stress(ERS). Methods:Thirty-two Sprague-Dawley rats were randomly divided into a control group,a CUMS group,an escitalopram(ESC)group,and an EA group.Except for the control group,rats in other groups were exposed to CUMS.From the 1st day of modeling,the EA group was treated with EA at Baihui(GV20)and Yintang(GV29)every day,15 min each time;the ESC group was given intragastric intervention[ESC 10 mg/(kg·bw)every day],both for 28 d.Body mass measurement,open field test(OFT),and sucrose preference test(SPT)in each group were performed before(day 0)and after experiment(day 28)to record body mass growth,sugar preference index,and total distance and duration of central area in OFT.The protein expression levels of glucose-regulated protein 78(GRP78),caspase-12,and C/EBP homologous protein(CHOP)in the hippocampus and frontal cortex were detected by stain-free total protein normalization method of Western blotting.Meanwhile,the TdT-mediated dUTP-biotin nick end labeling assay was performed to determine the percentage of cell death in the frontal cortex. Results:After EA at Baihui(GV20)and Yintang(GV29),the body mass growth,sugar preference index,and total distance and duration of central area in OFT were effectively improved(P<0.05 or P<0.01);compared with the CUMS group,the expression levels of GRP78 and CHOP in the hippocampus,and caspase-12 and CHOP in the prefrontal cortex of rats were significantly reduced(P<0.05),and the apoptosis rate of cells in the prefrontal cortex decreased significantly(P<0.05). Conclusion:EA at Baihui(GV20)and Yintang(GV29)can significantly mitigate behavioral deficits of rats with CUMS-induced depression.The mechanism may be related to adjusting the ERS and inhibiting cell apoptosis.