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

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models

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 1

Genetic deletion of DAGLα reduces voluntary alcohol intake.

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Genetic deletion of DAGLα reduces voluntary alcohol intake. (A) Schemati...
(A) Schematic of the 2BC EtOH drinking paradigm for DAGLα–/– mice. In male and female DAGLα–/– (DAGLα KO) mice, (B and C) EtOH preference and (D and E) consumption were lower than in WT mice. Male DAGLα–/– maintained lower EtOH preference (B) and consumption (D) throughout the experiment, whereas females reached WT levels in both measures by week 4 (C and E). (F and G) Male and female DAGLα–/– mice showed no difference in total fluid consumption. Data analyzed by repeated-measure 2-way ANOVA, followed by a Holm-Šidák test for multiple comparisons between genotypes. Sample size n, P, and F values for main effects of genotype, 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.