A research team that included six BBRF grantees has reported encouraging results in animal-model tests exploring a potential new treatment for alcohol use disorder (AUD).

The team used two methods—genetic and pharmacological—to inhibit the action of an enzyme called DAGL (diacylglycerol lipase) in mouse models of AUD. DAGL plays an essential role in the synthesis of a molecule called 2-AG. Past research has shown that the release of 2-AG from neurons in the brain’s reward system is directly correlated with the intake of alcohol.

The team’s hypothesis was that inhibiting DAGL would result in a reduction in the release of 2-AG and a corresponding decrease in alcohol consumption in mice which had become accustomed to drinking alcohol. This proved to be the case, in a variety of mouse models of AUD related to different aspects of AUD in humans.

The study reporting the results appeared in The Journal of Clinical Investigation. The team was led by Sachin Patel, M.D., Ph.D., a 2015 BBRF Independent Investigator at Vanderbilt University.

The work of Dr. Patel’s team proceeds from extensive knowledge about the body’s endocannabinoid system—naturally occurring compounds (2-AG is one) that are heavily involved in processes relevant to AUD, including the processing of rewards, reaction to stress, and the modulation of affect.

Attempts have been made to target one of the cellular receptors for endocannabinaoids, called the CB1 receptor. Compounds that inhibit or block that receptor have been tested in mouse models of addiction and found to inhibit the animals’ self-administration of alcohol, as well as other drugs of abuse. One such compound was marketed for a time in Europe before being withdrawn due to harmful side effects.

The insight of Dr. Patel’s team was to target DAGL instead of the CB1 receptor where 2-AG binds. Using a pharmaceutical compound called DO34, which inhibits the DAGL enzyme needed to generate 2-AG, they found that in mouse models of AUD, alcohol consumption was decreased—importantly, without generating side effects such as anxiety and depression caused by drugs that block the CB1 receptor.

The DO34 compound not only reduced alcohol consumption by the mice; it also reduced their “preference,” a term that refers to the phenomenon in which an animal prefers to consume alcohol even when water is also freely available.

Experimentally deleting the gene that encodes the DAGL enzyme had the same impact in mice: they voluntarily consumed less alcohol and showed reduced preference for it vs. water. In other experiments, positive results were obtained when DAGL inhibition was tested in mice modeling various other aspects of AUD, suggesting to the team that targeting the enzyme “may represent an effective approach to the treatment of AUD across a spectrum of severity.” Based on their experiments, they recommend that development of a potent and selective DAGL inhibitor should be a high [research] priority.”

There is room for considerable refinement of the drug used in the tests, in part because DAGL exists in two variant configurations in the body, and in part because the way 2-AG affects anxiety and depression behaviors “is highly dependent on context, such as alcohol-use history,” the team points out.

The researchers note another potentially positive implication of their work. Since expression of the genes that encode DAGL varies among individuals, potentially impacting its availability in the body, it may be possible to use such expression as an indicator of individual susceptibility to AUD—or, for predicting individual responsiveness to DAGL-inhibiting drugs like DO34 which may be used to treat AUD.

Other members of the team included: Danny G. Winder, Ph.D., 2013 BBRF Distinguished Investigator and 2002 Young Investigator; Cody Siciliano, Ph.D., 2017 BBRF Young Investigator; Samuel Centanni, Ph.D., 2018 BBRF Young Investigator; Snigdha Mukerjee, Ph.D., 2004 BBRF Young Investigator; and Gaurav Bedse, Ph.D., 2017 BBRF Young Investigator.