BRIEF RESEARCH REPORT article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1626031
This article is part of the Research TopicPotential Therapeutic Targets in Alcohol Use Disorder: Insights from Recent Preclinical StudiesView all articles
Fenofibrate treatment during withdrawal reverses symptoms of ethanol-induced depression in male rats
Provisionally accepted- Institute of Biomedical Sciences, Faculty of Health Sciences, Autonomous University of Chile, Santiago, Chile
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Alcohol use disorder (AUD) and major depression frequently co-occur, both involving significant neuroinflammatory components. Current treatments are often ineffective in addressing AUD-related depression, highlighting the need for novel therapeutic approaches. Previous studies showed that fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, reduces voluntary alcohol intake and attenuates neuroinflammation and oxidative stress in alcohol-preferring rats. This study investigated whether fenofibrate administered during alcohol withdrawal could alleviate ethanolinduced depressive symptoms and neurobiological alterations.Male rats received ethanol (1 g/kg, i.p.) on alternate days for three weeks; controls received saline. During a two-week withdrawal period, half of the ethanol-treated rats received fenofibrate (50 mg/kg/day) for the final five days. Behavioral assessments included the open field, tail suspension, and sucrose intake tests. RT-qPCR evaluated proinflammatory cytokine and brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) and hippocampus, while Golgi staining assessed dendritic arborization.Ethanol exposure increased anxiety and immobility in behavioral tests, consistent with depressive-like behaviors, and elevated TNF-α, IL-1β, and IL-6 levels. Fenofibrate reversed these behavioral and molecular effects, normalized PFC BDNF expression, and partially restored dendritic complexity. However, ethanol-induced reductions in sucrose intake after withdrawal-reflecting anhedonia-were not reversed by fenofibrate.These findings suggest that fenofibrate mitigates ethanol-induced depressive-like behaviors and neurobiological dysfunctions through anti-inflammatory and neuroprotective mechanisms. Given its established clinical use and safety profile as an FDA-approved drug, fenofibrate shows promise as a translational therapeutic adjunct for treating depression in individuals with AUD.
Keywords: alcohol use disorder, Depression, Fenofibrate, Neuroinflammation, BDNF, PPAR-α, dendritic arborization
Received: 09 May 2025; Accepted: 29 Jul 2025.
Copyright: © 2025 León, Vásquez-Ulloa, Marambio-Ruiz, Pérez-Reytor and Karahanian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Diliana Pérez-Reytor, Institute of Biomedical Sciences, Faculty of Health Sciences, Autonomous University of Chile, Santiago, Chile
Eduardo Karahanian, Institute of Biomedical Sciences, Faculty of Health Sciences, Autonomous University of Chile, Santiago, Chile
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