Shahrekord University of Medical Sciences Journal of Shahrekord University of Medical Sciences 2717-0071 27 2 2025 06 29 Possible involvement of the PI3K/Akt/mTOR signaling pathway in the antidepressant-like effects of modafinil in a mouse model of maternal separation stress 60 66 10.34172/jsums.916 EN Zahra Lorigooini https://orcid.org/0000-0003-0844-7571 Hossein Tahmasebi Dehkordi https://orcid.org/0000-0003-4625-6258 Maryam Hashemi-Shahraki https://orcid.org/0000-0002-2370-2457 Hamid Reza Shahamat https://orcid.org/0009-0002-2232-6223 Elham Zarean https://orcid.org/0000-0001-7294-6709 Hossein Amini- khoei https://orcid.org/0000-0002-5029-9632 Journal Article 10.34172/jsums.916 2023 09 09 2023 11 20 Background and aims: Depression is a widespread mental disorder. Maternal separation (MS) stress during early life increases the risk of depression. Modafinil (MOD) exhibits potential antidepressant-like properties, but its underlying molecular mechanisms remain unclear. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is implicated in neuropsychiatric disorders. This study aimed to investigate the role of the PI3K/Akt/mTOR pathway in the antidepressant-like effects of MOD in MS mice, offering potential insights into new therapeutic targets for depression treatment. Methods: In this study, 50 male NMRI mice were divided into five groups (n=10). The control group received normal saline, while the MS groups received normal saline and MOD at 25 mg/kg, 50 mg/kg, and 75 mg/kg for seven days. The counting open field test (OFT), forced swimming test (FST), and splash test were conducted to assess depression in rodents. The expression of PI3K, AKT, and mTOR genes was evaluated in the hippocampal tissue with real-time polymerase chain reaction (RT-PCR). Results: The results revealed that MS could induce depressive-like behaviors in mice. MOD administration significantly diminished immobility time in the FST at all doses (P<0.001) and amplified cleaning time in the splash test at doses of 25 mg/kg (P<0.01), 50 mg/kg (P<0.001), and 75 mg/kg (P<0.001). Additionally, MOD noticeably downregulated the expression of PI3K, AKT, and mTOR genes in the hippocampus at all doses (P<0.001). Conclusion: MOD possessed antidepressant-like properties in maternally separated mice. MOD could effectively ameliorate depressive-like behaviors and suppress the hippocampal expression of PI3K/AKT/mTOR genes. However, future studies are warranted to find the exact and more mechanisms of action of MOD in depression.