Zahra Lorigooini
, Hossein Tahmasebi Dehkordi
, Maryam Hashemi-Shahraki
, Hamid Reza Shahamat
, Elham Zarean
, Hossein Amini- khoei
*
Abstract
Background and Aims: Depression is a widespread and incapacitating mental disorder. Maternal separation (MS) stress during early life increases the risk of depression. Modafinil (MOD), a wake-promoting agent, exhibits potential antidepressant-like properties, but its underlying molecular mechanisms remain unclear. The PI3K/Akt/mTOR signaling pathway is implicated in neuropsychiatric disorders, including depression. This study aims to investigate the role of the PI3K/Akt/mTOR pathway in the antidepressant-like effects of MOD in maternally separated 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 maternal separation (MS) groups received normal saline along with MOD at 25, 50, and 75mg/kg for seven days. Tests related to assessment of depression in rodents counting open field test (OFT), forced swimming test (FST), and splash test were conducted. Gene expression of PI3K, AKT, and mTOR evaluated in the hippocampal tissue with Real-time PCR. Results: The results revealed that MS induced 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 (P<0.01), 50 (P<0.001), and 75mg/kg (P<0.001). Additionally, MOD markedly 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 effectively ameliorated depressive-like behaviors and suppressed the expression of the hippocampal expression of PI3K/AKT/mTOR genes. However, future studies warranted to find exact and more mechanisms of action of MOD in depression.