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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 2

Pharmacological inhibition of DAGL by DO34 reduces voluntary alcohol intake and produces similar brain lipid profiles in naive and chronically drinking C57BL/6J mice.

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Pharmacological inhibition of DAGL by DO34 reduces voluntary alcohol int...
(A) Schematic of 2BC EtOH drinking paradigm for mice receiving DO34 treatment. (B) DO34 (3 days) nonsignificantly reduced EtOH preference in male mice and (C) significantly reduced EtOH preference in female mice. (D and E) DO34 reduced EtOH consumption in both (D) male and (E) female mice. (F and G) DO34 had no effect on total fluid consumption in (F) male or (G) female WT mice. (H) The analog compound DO53 (5 days) had no effect on EtOH preference in female mice. (I) DO53 reduced EtOH consumption in female mice, and this was paralleled by (J) a nonspecific reduction in total fluid consumption. (K–O) DO34 (4 days) depleted brain (K) 2-AG, (L) AA, (M) PGE2, and (N) PGD2 levels similarly in naive and chronically (6 weeks, 20% EtOH) drinking mice, with (O) no effect on AEA levels. B–G: Data analyzed by 1-way ANOVA for time points 39–44, followed by a Holm-Šidák test for multiple comparisons to baseline (day 39) control. H–J: Data analyzed by 1-way ANOVA for averaged baseline (days 36–39) and individual treatment days, followed by a Holm-Šidák test for multiple comparisons to averaged baseline. K–O: Data analyzed by 2-way ANOVA, followed by a Holm-Šidák test for multiple comparisons between vehicle and DO34. All DO34 and DO53 treatments were dosed at 50 mg/kg. Sample size n, P, and F values for main effects of drug treatment and significance for post hoc multiple comparisons are reported in the graphs. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data are presented as mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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