Endocannabinoid 2-AG Plays Critical Role In Stress Resilience

2-arachidonoylglycerol (2-AG), a natural signaling molecule that activates cannabinoid receptors in the brain, plays a key role in the ability to adapt to repeated and acute exposures to traumatic stress, researchers at Vanderbilt University Medical Center report.

The findings could have wide implications for the treatment and prevention of anxiety and mood disorders, including major depression and post-traumatic stress disorder (PTSD). Sachin Patel, M.D., Ph.D., director of the Division of Addiction Psychiatry at Vanderbilt University School of Medicine and the paper’s corresponding author, said:

“The study suggests that deficiencies in natural cannabinoids could result in a predisposition to developing PTSD and depression. Boosting this signaling system could represent a new treatment approach for these stress-linked disorders.”

Brain Cannabinoid Signalling

Patel, the James G. Blakemore Professor of Psychiatry, received a Presidential Early Career Award for Scientists and Engineers last year for his studies of the endocannabinoid family of signaling molecules that activate the CB1 and CB2 cannabinoid receptors in the brain.

Tetrahydrocannabinol (THC), the active compound in marijuana, binds the CB1 receptor, which may explain why relief of tension and anxiety is the most common reason cited by people who use marijuana chronically.

Patel and his colleagues previously have found CB1 receptors in the amygdala, a key emotional hub in the brain involved in regulating anxiety and the fight-or-flight response. They also showed in animal models that anxiety increases when the CB1 receptor is blocked by a drug or its gene is deleted.

More recently, they reported anxiety-like and depressive behaviors in genetically modified mice that had an impaired ability to produce 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid. When the supply of 2-AG was increased by blocking an enzyme that normally breaks it down, the behaviors were reversed.

2-AG Stress-resilience

In the current study, the researchers tested the effects of increasing or depleting the supply of 2-AG in the amygdala in two populations of mice. One was previously determined to be susceptible to the adverse consequences of acute stress, and the other population exhibited stress-resilience.

Supplementing the 2-AG supply increased the proportion of stress-resilient mice overall and promoted resilience in mice that were previously susceptible to stress, whereas depleting 2-AG rendered previously stress-resilient mice susceptible to developing anxiety-like behaviors after exposure to acute stress.

Together these results suggest that 2-AG signaling through the CB1 receptor in the amygdala promotes resilience to the adverse effects of acute traumatic stress exposure, and support previous findings in animal models and humans suggesting that 2-AG deficiency could contribute to development of stress-related psychiatric disorders.

Marijuana use is highly cited by patients with PTSD as a way to control symptoms. Similarly, the Vanderbilt researchers found that THC promoted stress-resilience in previously susceptible mice.

But marijuana use in psychiatric disorders has obvious drawbacks, including possible addiction and cognitive side effects, among others. The Vanderbilt study suggests that increasing production of natural cannabinoids may be an alternative strategy to harness the therapeutic potential of this signaling system.

If further research finds that some people with stress-related mood and anxiety disorders have low levels of 2-AG, replenishing the supply of this endocannabinoid could represent a novel treatment approach and might enable some of them to stop using marijuana, the researchers concluded.

Rebecca J. Bluett, Rita Báldi, Andre Haymer, Andrew D. Gaulden, Nolan D. Hartley, Walker P. Parrish, Jordan Baechle, David J. Marcus, Ramzi Mardam-Bey, Brian C. Shonesy, Md. Jashim Uddin, Lawrence J. Marnett, Ken Mackie, Roger J. Colbran, Danny G. Winder & Sachin Patel
Endocannabinoid signalling modulates susceptibility to traumatic stress exposure
Nature Communications 8, Article number: 14782 (2017) doi:10.1038/ncomms14782

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