Northwestern scientists have identified, for the first time, a specific group of neurons — cells in the brain — that appear to contribute to anxiety caused by cannabinoid drugs, particularly when those drugs are combined with stressful conditions. Cannabinoids are a category of substances that includes THC, the main psychoactive ingredient in cannabis.
To investigate how cannabinoids influence fear and anxiety, researchers exposed mice to a threatening smell derived from fox urine. Before encountering the odor, the animals were given either a placebo or a synthetic cannabinoid drug.
Mice that received the cannabinoid froze more frequently and spent less time exploring the predator scent. Researchers traced these anxiety related behaviors to increased activity in a small population of brain cells known as somatostatin neurons. These neurons are located in the central amygdala, an area of the brain involved in processing fear and stress.
When the researchers genetically silenced the somatostatin neurons, the mice that received the cannabinoid became less likely to avoid the predator odor. The result suggested that these cells play an important role in producing the anxious response.
“The results of this study could explain why a good trip can turn bad pretty quickly if people consume too much cannabis or the situation they are in turns stressful or scary,” said study senior author Dr. Sachin Patel, chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine.
The study was published on Oct. 2 in Nature Communications.
Tracking the Brain During a Threat
Patel and his colleagues gave mice several different doses of the synthetic cannabinoid and measured their reactions to the predator odor. The researchers recorded how much time the animals spent near the scent and whether they responded by freezing or fleeing.
At the same time, the team monitored activity inside the brain by implanting a small microscope into the mice’s brain.
Researchers also studied brain tissue to determine how cannabinoids changed communication between neurons. Their experiments showed that the drug weakened a natural brain mechanism that normally acts as a “brake” on somatostatin neurons. With that restraint reduced, the neurons became more active.
“Higher doses of cannabinoids and environmental stress worked together to synergistically release the ‘brake’ on the central amygdala, which in turn drove excessive anxiety,” Patel explained.
Why Cannabis and Anxiety Matter
Cannabis use in the U.S. has steadily increased in recent years. At the same time, emergency department visits involving adverse effects from the drug have also risen.
Previous studies have found an association between cannabis use and a higher long term risk of anxiety. Anxiety and mood disorders are also on the rise globally.
“Understanding how cannabis affects brain function to generate its psychoactive effects could ultimately reveal new ways to counteract negative consequences should they arise in some people,” Patel said.
The researchers believe the findings may also have relevance beyond cannabis related side effects. Patel said the same neurons could potentially represent a broader target for understanding or reducing anxiety.
“Suppressing the activity of somatostatin neurons in the central amygdala could represent a final pathway for reducing anxiety symptoms, not just in the context of cannabis side effects,” he explained.
Other Northwestern co-authors are Farhana Yasmin, Saptarnab Naskar, Danyal Zaidi, Isaac Kandil, Michelle Kwon and Dr. Luis Rosas-Vidal.
The study is titled, “Cannabinoid Modulation of Central Amygdala Population Dynamics During Threat Investigation.” It was supported by the National Institutes of Health (grants MH100785 and K08 MH126166) and the Brain & Behavior Research Foundation’s Young Investigator Awards.
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