Chronic ethanol exposure induced depressive-like behavior in male C57BL/6 N mice by downregulating GluA1

Chronic ethanol exposure can increase the risk of depression. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is a key factor in depression and its treatment. The study was conducted to investigate the depressive-like behavior induced by chronic ethanol exposure in mice and to explore the mechanism in cells. To establish the chronic ethanol exposure mouse model, male C57BL/6 N mice were administered 10% (m/V) and 20% (m/V) ethanol as the only choice for drinking for 60 days, 90 days and 180 days. Depressive-like behavior in mice was confirmed by the forced swimming test (FST). Ethanol-induced changes in the mouse hippocampus were indicated by Western blotting, qPCR and Fluoro-Jade C (FJC) staining. We confirmed that 90- and 180-day ethanol exposure can lead to depressive-like mouse behavior, cell apoptosis, neuronal degeneration, a reduction in GluA1 and brain-derived neurotrophic factor (BDNF) expression, and an increase in IL-6 and IL-1 beta in the mouse hippocampus. GluA1 silencing and overexpression models of SH-SY5Y cells were established for further investigation. The cells were treated with 100 mM and 200 mM ethanol for 24 h. Ethanol exposure decreased cell viability and the expression of BDNF and increased the cell apoptosis rate and the expression of BAX, cleaved caspase-3, IL-1 beta and IL-6. GluA1 silencing aggravated ethanol-induced changes in cell viability and apoptosis and the expression of BDNF, BAX and cleaved caspase-3, and GluA1 overexpression attenuated these changes. Neither the silencing nor overexpression of GluA1 had an effect on ethanol-induced increases in IL-1 beta and IL-6. Our results indicated that chronic ethanol exposure induced depressive-like behavior in male C57BL/6 N mice by downregulating GluA1 expression.