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Updated: May 4, 2026
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Murine Drinking Models in the Development of Pharmacotherapies for Alcoholism: Drinking in the Dark and Two-bottle Choice
Published on: January 7, 2019
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Peripheral alcohol metabolism dictates ethanol consumption and drinking microstructure in mice
Bryan Mackowiak1, David L Haggerty2, Taylor Lehner1
1Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Biorxiv : the Preprint Server for Biology
|June 26, 2025
Summary
Alcohol dehydrogenase 1 (ADH1) significantly impacts ethanol consumption and metabolite levels. Inhibiting or removing ADH1 reduces ethanol intake and alters drinking patterns, revealing its critical role in alcohol use disorder (AUD).
Area of Science:
- Biochemistry and Metabolism
- Neuroscience and Behavioral Science
- Pharmacology
Background:
- Ethanol metabolism, primarily through alcohol dehydrogenase (ADH) and aldehyde dehydrogenases (ALDHs), influences ethanol's physiological and behavioral effects.
- Understanding the interplay between ethanol and its metabolites is crucial for developing interventions for alcohol use disorder (AUD).
- Alcohol dehydrogenase 1 (ADH1), responsible for metabolizing over 90% of ingested ethanol, plays a key role in peripheral ethanol processing and downstream behaviors.
Purpose of the Study:
- To investigate how ADH1 modulates ethanol metabolite distribution.
- To determine the impact of ADH1 on ethanol-driven behaviors.
- To elucidate the role of ADH1 in ethanol consumption patterns.
Main Methods:
- Ethanol consumption was assessed in drinking-in-the-dark (DID) and two-bottle choice (2BC) paradigms using alcohol dehydrogenase 1 (ADH1) knockout (KO) mice and wild-type (WT) mice.
- Ethanol metabolite concentrations (ethanol, acetaldehyde, acetate) were measured after ADH1 inhibition (fomepizole, 4-MP) or in ADH1 KO mice.
- Drinking microstructure was analyzed using lickometry to assess drinking patterns and bout structures.
Main Results:
- ADH1 KO mice and mice treated with an ADH1 inhibitor (4-MP) exhibited significantly reduced ethanol consumption and preference in both DID and 2BC paradigms.
- ADH1 inhibition or knockout led to increased blood ethanol levels and altered peripheral acetaldehyde and acetate concentrations.
- Ethanol accumulation was higher in ADH1-compromised mice, and drinking microstructure analysis revealed altered temporal drinking patterns and abnormal bout structures, leading to lower overall consumption.
Conclusions:
- ADH1-mediated ethanol metabolism is a critical determinant of ethanol consumption and preference.
- The study highlights a significant knowledge gap regarding how ethanol and its metabolites interact to drive consumption behaviors.
- Targeting ADH1 activity could be a potential strategy for managing alcohol use disorder.
