To investigate the possible intrauterine mechanism of increased susceptibility of depression in adult female rats offspring resulting from prenatal nicotine exposure (PNE). Methods: Pregnant Wistar rats were randomly divided into control and PNE groups. PNE rats were given nicotine (2 mg/kg·d) by subcutaneous injection from the 9th day to the 20th day of gestation. Brain sections were taken of some offspring rats on the 20th day of pregnancy, and NeuN staining was performed to observe morphological changes in the prefrontal cortex and hippocampus. The other offspring rats were raised to 3 months old and given chronic unpredictable mild stimulation (CUMS). The behavioral changes of female offspring rats were observed before and after stimulation. Real-time quantitative PCR was used to detect expression of genes related to synapse formation in the prefrontal cortex and hippocampus. Results: Compared with the control group, the female rats in the PNE group showed significant decrease in total distance traveled and total rate after CUMS in the open-field test (P<0.05). The frequency of upright position decreased also (P<0.05). However, the quantity of feces was increased in the PNE group (P<0.05). In the forced swimming test, adult female offspring in the PNE group showed significantly longer immobility time than those in the control group (P<0.01), displaying depressive behavior. Fetal offspring in the PNE group showed thinner prefrontal cortex and unclear cell layers in the hippocampus with incomplete axons. The mRNA expression of NR1, NR2A, NR2B, Syn I, and Snap25 in the prefrontal cortex and hippocampus was significantly decreased after CUMS in adult offspring of the PNE group compared to those of the control group (P<0.01). Conclusion: Exposure to nicotine during pregnancy in rats leads to an increased susceptibility to depression in their adult female offspring, which may be related to decreased expression of genes involved in the development of neurons and synapses in the prefrontal cortex and hippocampus, resulting in changes in the structure and function of the prefrontal cortex and hippocampus