Modulatory effects of Withania somnifera on depression and neurochemical alterations during ethanol withdrawal in rats

Abstract

Chronic ethanol consumption causes alcohol use disorders, leading to depressive-like behavior, cognitive deficits, and neurochemical dysregulation. Ethanol withdrawal disrupts GABAergic and glutamatergic neurotransmission, promoting neuroadaptations that exacerbate behavioral and physiological deficits. Withania somnifera (WS) (Ashwagandha), rich in withanolides, exhibits antioxidant, anti-inflammatory, and neuroprotective properties. In this study WS leaf extract effect on depression brought on by ethanol withdrawal in male Sprague Dawley rats weighing 200–250 g were evaluated. There were six groups of rats: Control, disease control, standard (MK-801, intraperitoneally, 0.1 mg/kg), and WS treatment groups (orally, 50, 100, 200 mg/kg). For a period of 28 days, a graded ethanol liquid diet was followed by withdrawal. Open-field and forced swim tests were used for behavioral evaluations, while brain tissues were analyzed for Pro-inflammatory cytokines (Tumor necrosis factor-alpha, interleukin-6), oxidative stress markers (malondialdehyde, nitrite, glutathione, catalase), neurotransmitters (GABA, glutamate, dopamine), and hippocampal histology. The data were assessed using a one-way analysis of variance and the Bonferroni post hoc test (P < 0.05). Ethanol withdrawal induced depressive-like behavior, neurotransmitter imbalance, oxidative stress, elevated cytokines, and hippocampal degeneration. WS treatment dose-dependently reversed these effects, with the 200 mg/kg dose producing maximal neuroprotective outcomes comparable to MK-801. These results indicate that WS leaf extract possesses neuroprotective, antidepressant-like, antioxidant, and anti-inflammatory activities, restoring behavioral, neurochemical, and histological parameters, underlining its possible as a natural therapeutic for ethanol withdrawal management.