{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T01:07:21Z","timestamp":1792976841161,"version":"4.5.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Alcohol use disorder (AUD) is associated with dysregulation of glutamatergic and dopaminergic signaling within the nucleus accumbens (NAc), contributing to withdrawal syndrome, craving, and relapse. Fenofibrate, an agonist of the peroxisome proliferator-activated receptor alpha (PPAR\u03b1), reduces alcohol intake; however, its effects on NAc neurotransmission and the relative contributions of central versus peripheral mechanisms remain unclear. Here, we investigated whether fenofibrate administration initiated during alcohol withdrawal and continued throughout reaccess reduces relapse drinking, and whether this effect involves normalization of glutamate and dopamine in the NAc. Fenofibrate treatment during withdrawal produced a sustained reduction in alcohol consumption throughout a 14-day relapse period in high-drinker female rats. This effect was abolished by systemic co-administration of the PPAR\u03b1 antagonist GW6471. Fenofibrate increased hepatic catalase activity and upregulated the glutamate transporter GLT-1 in the NAc, while dopamine transporter (DAT) protein levels remained unchanged. When GW6471 was administered intracerebroventricularly to block central PPAR\u03b1 activation selectively, the reduction in alcohol intake was only partially attenuated, indicating that approximately one-third of fenofibrate\u2019s effect is centrally mediated, whereas two-thirds result from peripheral mechanisms. No-net-flux microdialysis showed that fenofibrate enhanced uptake rates for both glutamate and dopamine in the NAc. Steady-state extracellular glutamate levels were unchanged, whereas extracellular dopamine levels were significantly reduced, consistent with increased functional DAT activity. These findings demonstrate that fenofibrate reduces relapse-like alcohol consumption through a combination of peripheral and CNS PPAR\u03b1-dependent mechanisms, restoring key aspects of glutamatergic and dopaminergic homeostasis in the NAc, highlighting PPAR\u03b1 activation as a promising therapeutic strategy for AUD.<\/jats:p>","DOI":"10.3389\/fphar.2026.1792426","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:42:35Z","timestamp":1774248155000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Fenofibrate restores glutamatergic and dopaminergic homeostasis in the nucleus accumbens and reduces alcohol relapse in rats"],"prefix":"10.3389","volume":"17","author":[{"given":"Eduardo","family":"Isla","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Aut\u00f3noma de Chile","place":["Santiago, Chile"]},{"name":"Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Guti\u00e9rrez-Vega","sequence":"additional","affiliation":[{"name":"Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders","place":["Santiago, Chile"]},{"name":"Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Elena","family":"Quilaqueo","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Herrera-Marschitz","sequence":"additional","affiliation":[{"name":"Interdisciplinary Nucleus of Pharmacology & Immunology, Institute of Biomedical Sciences ICBM, Faculty of Medicine, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Elena","family":"Quintanilla","sequence":"additional","affiliation":[{"name":"Interdisciplinary Nucleus of Pharmacology & Immunology, Institute of Biomedical Sciences ICBM, Faculty of Medicine, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Morales","sequence":"additional","affiliation":[{"name":"Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders","place":["Santiago, Chile"]},{"name":"Interdisciplinary Nucleus of Pharmacology & Immunology, Institute of Biomedical Sciences ICBM, Faculty of Medicine, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diliana","family":"P\u00e9rez-Reytor","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Aut\u00f3noma de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Rivera-Meza","sequence":"additional","affiliation":[{"name":"Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders","place":["Santiago, Chile"]},{"name":"Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, Universidad de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Karahanian","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Aut\u00f3noma de Chile","place":["Santiago, Chile"]},{"name":"Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"107454","DOI":"10.1016\/j.phrs.2024.107454","article-title":"Efficacy of medications for the treatment of alcohol use disorder (AUD): a systematic review and meta-analysis considering baseline AUD severity","volume":"209","author":"Agabio","year":"2024","journal-title":"Pharmacol. 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