Eric Hopton for redOrbit.com – Your Universe Online
Understanding just what happens in the brain when cannabis users get “high” is an essential part of the fight against drug dependency. A study by scientists at Vanderbilt University Medical Center study has now provided insights into that process.
The latest research from Vanderbilt found that “replenishing the supply of a molecule that normally activates cannabinoid receptors in the brain could relieve mood and anxiety disorders and enable some people to quit using marijuana.”
When users take cannabis, they are “turned on” by the active ingredient in marijuana. But, in addition, certain “cannabinoid receptors” – called endocannabinoids – are activated by compounds in the brain. These include anandamide (AEA) and 2-arachidonoylglycerol (2-AG). 2-AG is the most abundant of these endocannabinoids.
Sachin Patel, M.D., Ph.D., and his Vanderbilt colleagues carried out the research, which was published on Nov. 26 in the online edition of the journal Cell Reports.
In the first part of the study the team developed a genetically modified mouse which had “impaired ability to produce 2-AG in the brain.” They discovered that those mice showed anxiety-like behaviors. Female mice also exhibited behavior patterns which were suggestive of depression.
In the next stage of the experiment, an enzyme that normally breaks down 2-AG was blocked and the supply of the endocannabinoid was restored to normal levels. The anxiety and depressive behaviors were reversed.
Though some previous clinical studies have discovered reduced peripheral 2-AG levels in patients with posttraumatic stress disorder and women with major depression, no firm causal link has been established. Further research is now needed to confirm that people who are anxious and depressed have low levels of 2-AG.
Though these latest findings suggest a close association between 2-AG signaling and affective pathology, the researchers point out that “a causal relationship between endogenous 2-AG signaling and the physiological expression of anxiety and depressive behaviors has not been demonstrated.” The team also stressed that this approach has not been tested in humans. Nevertheless, they believe that this method of “normalizing” 2-AG deficiency could eventually lead to a viable therapeutic option for treating mood and anxiety disorders.
Patel, who is the paper’s senior author and professor of Psychiatry and of Molecular Physiology and Biophysics at Vanderbilt, explains that, as “relief of tension and anxiety is the most common reason cited for chronic marijuana use,” restoring depleted levels of 2-AG could be a way to help habitual marijuana users kick the habit.
It is known that chronic use of marijuana down-regulates cannabinoid receptors, and, as a result, increases anxiety. This in turn can result in a kind of vicious cycle process where marijuana use increases relentlessly.
In previous research, Patel and his colleagues found cannabinoid receptors in the central nucleus of the amygdala mouse brains. The amygdala plays an important part in regulating anxiety. They also have found that chemically modified inhibitors of the COX-2 enzyme they developed “relieve anxiety behaviors in mice by activating natural “endocannabinoids.” These inhibitors did not cause the gastrointestinal side effects often associated with current COX-2 inhibitors.
COX-2 inhibitors, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) target the Cyclooxygenase (COX) enzymes which produce pro-inflammatory prostaglandins to relieve pain and inflammation. It has also been known for several years that COX-2 inhibition activates endocannabinoids.
The Vanderbilt team hopes this research could lead to clinical trials of potential new drugs in the next few years.
The current study was led by first authors Brian Shonesy, Ph.D., research fellow in the lab of Roger Colbran, Ph.D., professor of Molecular Physiology and Biophysics, and Rebecca Bluett, a graduate student in Patel’s lab.
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