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 for AUD 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 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 models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanolinduced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.

2-Arachodonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice

“…Our data and a recent study [20] confirm the preclinical efficacy of MAGL inhibition in the reduction of mechanical hypersensitivity associated with alcohol withdrawal. There is some evidence that MAGL inhibition can increase hedonic behavior [80, 81], however we have previously shown that MAGL inhibition did not increase alcohol consumption or preference in mice [82], and direct lateral habenula MAGL inhibition actually reduced operant alcohol self-administration [20]. Moreover, MAGL inhibition has been shown to reduce negative affective states induced by alcohol withdrawal [83].…”

“…DAGLα -/- mice exhibit more anxiety-like and depression-like behaviors at baseline [94, 95], and DO34 treatment after acute stress causes increased anxiety and depression-like behaviors [96]. Our lab has also shown DO34 impairs fear extinction in mice [97], and reduces alcohol consumption in a two-bottle choice paradigm [82]. However, little is known about the effects of inhibition of DAGL on pain processing.…”

“…Postsynaptic 2-AG is synthesized on-demand by the enzyme DAGL⍺ in neurons [90][91][92]. Pharmacological inhibition of DAGL via the compound DO34 results in dramatic decreases in brain 2-AG levels [82,93]. DAGL⍺ -/mice exhibit more anxiety-like and depression-like behaviors at baseline [94,95], and DO34 treatment after acute stress causes increased anxiety and depression-like behaviors [96].…”

Alcohol-Endocannabinoid Interactions: Implications for Addiction-Related Behavioral Processes

“…Indeed, recent studies are providing insight into the possible therapeutic relevance of DAGL inhibition in reducing alcohol consumption without precipitating negative affective behaviors associated with chronic alcohol exposure and withdrawal. 188 …”

Effects of Cannabinoid Exposure during Neurodevelopment on Future Effects of Drugs of Abuse: A Preclinical Perspective

“…Interestingly, and pertinent to this review, recent research has demonstrated how targeting specific levels of complex ECS signaling can prove beneficial. By inhibiting DAGL in rodents, researchers reduced overall alcohol consumption in a model of alcohol use disorder [ 63 ]. Additionally, it has been demonstrated that consumption of dietary fats alters the subsequent function of previously mentioned ECS units.…”