Neurons Involved in Generating Anxiety After Cannabinoid Drug Exposure Identified in Mice

Working with mice, Northwestern scientists have for the first time identified a set of neurons in the brain that play a role in generating anxiety after exposure to cannabinoid drugs, especially under stressful conditions. Cannabinoids are a class of substances that includes tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis and synthetic analogs.

Scientists exposed mice to a predator odor after giving them a placebo or a cannabinoid drug. Animals given the cannabinoid froze more and spent less time investigating the odor. Using small microscopes, scientists identified neurons activated by the drug that helped drive anxious behaviors. When those neurons were silenced the cannabinoid no longer triggered the same level of anxious behaviors.

The findings could help scientists better understand how cannabis exerts its psychoactive effects, and potentially point to strategies for holding back anxiety in affected individuals. The results could provide insights into strategies for reducing anxiety symptoms in other contexts, outside of cannabis use.

“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 Sachin Patel, MD, PhD, chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine.

Patel is senior and corresponding author of the team’s published paper in Nature Communications, titled “Cannabinoid modulation of central amygdala population dynamics during threat investigation.” In their paper the team concluded that their results “… could ultimately provide important insights into how cannabinoids augment threat reactivity and the interactions between cannabis use and anxiety disorders.”

Plant-derived cannabinoids are widely used for medicinal and recreational purposes, and exert broad-ranging behavioral and physiological effects on mood, anxiety, memory, appetite, and sleep, the authors noted. But they can also precipitate anxiety and panic reactions in people, and increase threat-related defensive responses in rodents. “Specifically, while tension and anxiety relief represent major reasons for cannabis use, paradoxical dose- and context-dependent increases in anxiety and panic are also well-documented, and some studies have suggested associations between cannabis use and the development and worsening of anxiety disorders, especially in heavy cannabis users.” However, they continued, Despite well-established research findings, “… how cannabinoids affect in vivo neural dynamics associated with threat-related behavior has not been examined.”

For their newly reported study the scientists exposed mice to a threatening odor. Before being exposed to the scent, derived from fox urine, the mice either received a placebo or a synthetic cannabinoid drug. Patel and colleagues tested several doses of the synthetic cannabinoid on mice and tracked how much time they spent near the predator odor, and whether they froze or fled from the scent.

To simultaneously record brain activity, the team implanted a small microscope into the mice’s brain. The results showed that mice receiving the cannabinoid drug froze more often and spent less time investigating the predator odor. These anxious behaviors were linked to the drug’s activation of a small group of somatostatin neurons (SOM) in the brain’s central amygdala (CeA), a region that processes fear and stress.

Importantly, when the scientists genetically silenced the somatostatin neurons, mice given the cannabinoid drug did not avoid the predator scent as much. The researchers also conducted brain tissue experiments to analyze how the cannabinoids affected interactions between neurons. They found that the drug weakened the brain’s natural “brake” on the somatostatin neurons, allowing them to become more active. “Our data suggest suppression of GABA release from local afferents onto CeA SOM neurons underlies cannabinoid effects on CeA SOM neurons,” they wrote.

“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 noted. “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, also noting that the findings could have implications beyond cannabis. “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.

Cannabis use in the U.S. has steadily increased in recent years and so have emergency department visits related to adverse effects from the drug. Previous studies have also found an association between cannabis use and increased risk of anxiety in the long term. What’s more, anxiety and mood disorders are also on the rise globally.

Commenting that their newly reported data begin to shed light on neural mechanisms subserving the “dark-side” adverse effects of cannabinoids, the authors concluded, “… we suggest cannabinoids could trigger context-dependent adverse anxiety and panic reactions, in part, via activation of CeA-related circuits and that cannabis-induced long-term adaptations in these circuits could contribute to observed associations between cannabis use and anxiety disorders.”

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