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Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models
Nathan D. Winters, … , Danny G. Winder, Sachin Patel
Nathan D. Winters, … , Danny G. Winder, Sachin Patel
Published July 22, 2021
Citation Information: J Clin Invest. 2021;131(17):e146861. https://doi.org/10.1172/JCI146861.
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Research Article Neuroscience Article has an altmetric score of 25

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models

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Abstract

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing, and alcohol intake is positively correlated with release of the eCB ligand 2-arachidonoylglycerol (2-AG) within the reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate-limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical mouse models, ranging from a voluntary free-access model to aversion-resistant drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal did not elicit anxiogenic and depression-like behavioral effects. Last, DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest that reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reducing alcohol consumption across the spectrum of AUD severity.

Authors

Nathan D. Winters, Gaurav Bedse, Anastasia A. Astafyev, Toni A. Patrick, Megan Altemus, Amanda J. Morgan, Snigdha Mukerjee, Keenan D. Johnson, Vikrant R. Mahajan, Md Jashim Uddin, Philip J. Kingsley, Samuel W. Centanni, Cody A. Siciliano, David C. Samuels, Lawrence J. Marnett, Danny G. Winder, Sachin Patel

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Figure 4

DO34 reduces reinstatement of EtOH drinking and does not precipitate negative affective phenotypes during protracted abstinence.

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DO34 reduces reinstatement of EtOH drinking and does not precipitate neg...
(A) DO34 (7 days) reduced preference and (B) consumption relative to vehicle upon reinstatement of 10% EtOH drinking after 5 weeks of drinking and 10 days of withdrawal. DO34 treatment was initiated 2 days before onset of reinstatement of EtOH access. (C) Schematic depicting 2BC drinking paradigm for behavioral testing in withdrawal. (D) EtOH preference and (E) consumption in mice tested in the withdrawal cohort. (F) EtOH-withdrawn mice showed a higher latency to first bite in the NIFS test, which was reduced to baseline with DO34 treatment. (G) DO34 treatment decreased immobility time in the FST in both groups. (H and I) DO34 treatment (H) increased the number of open-arm entries and (I) decreased immobility time in the EPM only in EtOH-withdrawn mice. A and B: Data analyzed by repeated-measure 2-way ANOVA, followed by a Holm-Šidák test for multiple comparisons between treatment conditions. F–I: Data were analyzed by 2-way ANOVA, followed by a Holm-Šidák test for multiple comparisons between all groups. DO34 was dosed at 50 mg/kg. Sample size n, P, and F values for main effects of (A and B) drug treatment or (F–I) EtOH × DO34 interaction, and significance for post hoc multiple comparisons are reported in graphs. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data are reported as mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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