It is unclear whether β-asarone has a good antidepressant effect and what is the main mechanism in Depression in Parkinson's disease (DPD) model rats.In this study, DPD model rats were screened from 6-OHDA induced rats by sucrose preference test (SPT) and forced swimming test (FST). DPD model rats were divided into eight groups: model group, pramipexole group, β-asarone low-dose group (β-asarone 7.5 group), β-asarone medium-dose group (β-asarone 15 group), β-asarone high-dose group (β-asarone 30 group), 3-MA group, rapamycin group, and PI3K inhibitor group. 28 days after the end of treatment, open field test (OFT), SPT and FST were conducted in rats. The level of α-synuclein (α-syn) in the striatum was determined by enzyme-linked immunosorbent assay (ELISA). The expression of Beclin-1, p62 in the striatum was determined by western blot. The expression of PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR, Beclin-1, and p62 in the hippocampus was determined by western blot. The spine density of neurons in the hippocampus was detected by golgi staining.The results showed that 4-week oral administration of β-asarone improve the motor and depressive symptoms of DPD model rats, and decrease the content of ɑ-syn in the striatum. β-asarone inhibited the expression of autophagy in the striatum of DPD model rats. Furthermore, β-asarone decreased the levels of Beclin-1 protein, increased the expression of p62, p-PI3K, p-AKT, and p-mTOR, and improved the density of neuron dendritic spine in the hippocampus.We concluded that β-asarone might improve the behavior of DPD model rats by activating the PI3K/Akt/mTOR pathway, inhibiting autophagy and protecting neuron.Copyright © 2024. Published by Elsevier B.V.