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 Therapeutics

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 5

DO34 prevents EtOH suppression of posterior VTA GABA transmission.

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DO34 prevents EtOH suppression of posterior VTA GABA transmission. (A) S...
(A) Schematic depicting recording strategy used to identify putative dopamine neurons exhibiting red fluorescence in the posterior VTA. (B) Left: Bath application of 100 mM EtOH reduced sIPSC frequency in vehicle-treated but not DO34-treated slices. Right: Example traces of sIPSC response to 100 mM EtOH in vehicle- or DO34-treated slices. (C) Relative proportions of sIPSC frequency (Freq.) response to 100 mM EtOH (defined as ≥10% change). DO34 treatment reduced the proportion of cells that exhibited a decrease in sIPSC frequency. One to 3 cells per mouse were included in analyses. Vehicle, n = 9 mice; DO34, n = 10 mice; 15 mice total (both conditions sampled from a subset of 4 mice). B: Data analyzed by 2-way ANOVA, followed by a Holm-Šidák test for multiple comparisons between baseline and EtOH application. C: Data analyzed by Fisher’s exact test for proportion of cells exhibiting reduced sIPSC frequency after EtOH application. Sample size n (cells), P, and F values for EtOH × DO34 interaction, and significance for post hoc multiple comparisons are reported in the graphs (*P < 0.05).