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A ketogenic diet reduces hepatic alcohol metabolism and alcohol consumption in rats.

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Title: A ketogenic diet reduces hepatic alcohol metabolism and alcohol consumption in rats.
Authors: Elvig SK; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.; Department of Pharmacology and Physiology, School of Medicine, University of Maryland, Baltimore, MD, USA., McGinn A; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Li X; Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA., Vendruscolo JCM; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Gomez JL; Biobehavioral Imaging and Molecular Neuropsychopharmacology Section, Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Pawlosky R; Office of the Scientific Director, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA., Mackowiak B; Laboratory of Liver Diseases, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA., Gonzalez L; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., King MT; Office of the Scientific Director, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA., Michaelides M; Biobehavioral Imaging and Molecular Neuropsychopharmacology Section, Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Gao B; Laboratory of Liver Diseases, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA., Volkow ND; Laboratory of Neuroimaging, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA., Koob GF; Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA., Wiers CE; Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. corinde.wiers@pennmedicine.upenn.edu., Vendruscolo LF; Stress and Addiction Neuroscience Unit, Intramural Research Program, National Institute on Drug Abuse. National Institutes of Health, Baltimore, MD, USA. leandro.vendruscolo@nih.gov.; Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. leandro.vendruscolo@nih.gov.
Source: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2026 Aug; Vol. 51 (9), pp. 1568-1576. Date of Electronic Publication: 2026 Mar 20.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8904907 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1740-634X (Electronic) Linking ISSN: 0893133X NLM ISO Abbreviation: Neuropsychopharmacology Subsets: MEDLINE
Imprint Name(s): Publication: 2003- : London : Nature Publishing Group
Original Publication: [New York, NY] : Elsevier, [c1987-
MeSH Terms: Liver*/metabolism , Alcohol Drinking*/metabolism , Ethanol*/administration & dosage , Ethanol*/blood , Ethanol*/metabolism , Diet, Ketogenic*, Alcohol Dehydrogenase/metabolism ; Brain/metabolism ; Glucose/metabolism ; NAD/metabolism ; Animals ; Male ; Female ; Rats ; Rats, Sprague-Dawley ; Self Administration
Abstract: Previous work showed that rats that were exposed to a high-fat, low-carbohydrate/protein ketogenic diet (KD) exhibited elevated blood alcohol levels following alcohol exposure compared with rats fed regular chow. Additionally, the administration of a KD prior to alcohol exposure (i.e., a history of KD) reduced alcohol consumption in alcohol-dependent rats that were no longer on the diet. In the present study, we investigated the mechanisms by which a KD alters alcohol metabolism and tested whether ongoing KD exposure reduces alcohol consumption in rats. We hypothesized that chronic KD exposure alters hepatic alcohol-metabolizing enzymes, slows alcohol metabolism, and reduces alcohol self-administration in alcohol-dependent rats. We found that male and female rats maintained on a KD had higher blood alcohol levels, lower hepatic alcohol dehydrogenase 1 protein levels, and a higher nicotinamide adenine dinucleotide [NAD+]/[NADH] ratio in the liver cytoplasm compared with chow-fed control rats. Furthermore, KD-fed rats demonstrated lower brain glucose uptake relative to chow-fed control rats. In a model of alcohol dependence, the KD reduced alcohol consumption in male, but not female, rats compared with chow-fed rats. These findings suggest that a KD alters brain energetics and alcohol metabolism, which may contribute to reduced alcohol consumption in male rats.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
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Grant Information: K99AA031746 U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA); ZIA DA000602 United States ImNIH Intramural NIH HHS; ZIA DA000644 United States ImNIH Intramural NIH HHS; ZIA-DA000644 U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA); R01 AA031570 United States AA NIAAA NIH HHS; K99 AA031746 United States AA NIAAA NIH HHS; R21 AA031337 United States AA NIAAA NIH HHS; R01AA031570 U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA); R21 AA031088 United States AA NIAAA NIH HHS; ZIA-DA000602 U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)
Substance Nomenclature: 3K9958V90M (Ethanol)
EC 1.1.1.1 (Alcohol Dehydrogenase)
IY9XDZ35W2 (Glucose)
0U46U6E8UK (NAD)
Entry Date(s): Date Created: 20260321 Date Completed: 20260721 Latest Revision: 20260726
Update Code: 20260726
PubMed Central ID: PMC13334472
DOI: 10.1038/s41386-026-02383-5
PMID: 41862734
Database: MEDLINE
Description
ISSN:1740-634X
DOI:10.1038/s41386-026-02383-5