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Pharmacol."],"abstract":"<jats:p>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-\u03b1) 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 ethanol-induced depressive symptoms and neurobiological alterations. Male rats received ethanol (1\u00a0g\/kg, i. p.) on alternate days for 3\u00a0weeks; controls received saline. During a 2-week withdrawal period, half of the ethanol-treated rats received fenofibrate (50\u00a0mg\/kg\/day) for the final 5\u00a0days. 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-\u03b1, IL-1\u03b2, 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\u2014reflecting anhedonia\u2014were 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.<\/jats:p>","DOI":"10.3389\/fphar.2025.1626031","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T05:27:48Z","timestamp":1754630868000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Fenofibrate treatment during withdrawal reverses symptoms of ethanol-induced depression in male rats"],"prefix":"10.3389","volume":"16","author":[{"given":"Marcelo","family":"Le\u00f3n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"V\u00e1squez-Ulloa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Marambio-Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diliana","family":"P\u00e9rez-Reytor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Karahanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e96864","DOI":"10.1371\/journal.pone.0096864","article-title":"Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals","volume":"9","author":"Bala","year":"2014","journal-title":"PloS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1515\/intox-2017-0006","article-title":"Animal tests for anxiety-like and depression-like behavior in rats","volume":"10","author":"Belovicova","year":"2017","journal-title":"Interdiscip. 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