How cannabinoids affected anxiety in mice

To investigate how cannabinoids affect fear and anxiety, researchers exposed mice to a threatening odor derived from fox urine. Before encountering the odor, the animals received either a placebo or a synthetic cannabinoid drug.

Mice given cannabinoids froze more often and spent less time exploring the scent of the predator. Researchers found that these anxiety-related behaviors were associated with increased activity in a small population of brain cells known as somatostatin neurons. These neurons are located in the central amygdala, a brain region involved in processing fear and stress.

When researchers genetically silenced the somatostatin neurons, mice given cannabinoids were less likely to avoid predator odors. The finding suggests that these cells play an important role in generating anxiety responses.

“The results of this study may explain why good trips quickly turn bad when people consume too much cannabis or the situation turns stressful or fearful,” said study lead author Dr. Sachin Patel, chair of the Department of Psychiatry and Behavioral Sciences at Northwestern University Feinberg School of Medicine.

The study was published October 2 in Nature Communications.

Tracking brain activity during a threat

Patel and his colleagues gave mice several different doses of synthetic cannabinoids and measured their responses to predator odors. The researchers recorded how long the animals spent near the scent and whether they froze or ran away in response.

At the same time, the research team implanted a miniature microscope into each mouse’s brain to observe neural activity.

Researchers also studied brain tissue to understand how cannabinoids altered communication between neurons. Their experiments showed that the drug weakened a natural brain mechanism that normally acts as a “brake” on somatostatin neurons. When that inhibition was relieved, the neurons became more active.

“High doses of cannabinoids and environmental stress worked synergistically to release the ‘brakes’ in the central amygdala, resulting in hyperanxiety,” Patel explained.

Why cannabis and anxiety matter

Cannabis use in the United States has steadily increased in recent years. At the same time, the number of emergency department visits linked to drug side effects is increasing.

Previous studies have found a link between cannabis use and an increased long-term risk of anxiety disorders. Anxiety and mood disorders are also on the rise worldwide.

“Understanding how cannabis affects brain function to produce its psychoactive effects may ultimately reveal new ways to counteract adverse effects when they occur in some people,” Patel said.

Researchers believe the finding may have implications beyond cannabis-related side effects. Patel said the same neurons could be a broader target for understanding and reducing anxiety.

“Suppressing the activity of somatostatin neurons in the central amygdala may be the ultimate route to reducing anxiety symptoms, not just in the context of cannabis side effects,” he explained.

Study authors and funding

Other Northwestern co-authors include Farhana Yasmin, Saptarnab Naskar, Danyal Zaidi, Isaac Qandil, Michelle Kwon, and Dr. Luis Rosas-Vidal.

The study is titled “Cannabinoid Modulation of Population Dynamics in the Central Amygdala During Threat Investigation.” The research was supported by the National Institutes of Health through grants MH100785 and K08 MH126166, as well as the Brain and Behavior Research Foundation Young Investigator Award.