The Body’s Own Cannabinoids May Help Us Respond to Stress

A new study has uncovered how circuits within the brain work to produce the body’s own cannabinoids in order to cope with stressful experiences. The research, which opens up new possibilities for the development of drugs for stress-related psychiatric disorders, is published in Cell Reports.

The relationship between stress and psychiatric conditions

Stress can increase the risk of developing or worsening psychiatric conditions, such as anxiety, major depressive disorder (MDD) or post-traumatic stress disorder (PTSD).

However, the brain can release chemical signals to help us cope with stressful experiences. Our brains can even produce molecules, known as endocannabinoids, that activate the same brain receptors stimulated by tetrahydrocannabinol (THC) from cannabis plants. The endocannabinoid system has been implicated in stress adaptation and fear responses, but until now, the exact mechanisms were not well understood.

Studies in humans and rodents have linked endocannabinoid signaling between the amygdala – a key emotional processing region in the brain – and the hippocampus – involved in learning and memory – in fear learning and stress-related states such as PTSD, while also suggesting that endocannabinoids play a role in resilience to stress.

“We showed almost 20 years ago that these endogenous cannabinoids were made upon stress exposure in mice, but these were crude measurements and lacked temporal and synaptic precision,” said Dr. Sachin Patel, senior author of the study and professor of psychiatry and behavioral sciences at Northwestern University, speaking to Technology Networks. “We did not know the types of brain activity required for the release of these molecules because we did not have the tools.”

Patel and colleagues have uncovered the underlying mechanisms of these brain circuits in an effort to study these connections in more detail, potentially aiding future drug development to treat stress-related psychiatric disorders by targeting the endocannabinoid system.

Monitoring endocannabinoids and stress responses

To understand more about how endocannabinoid release influences the brain’s circuitry, the researchers used a new protein sensor developed by study co-author Dr. Yulong Li, allowing them to detect the release of endogenous cannabinoids in the brain in real time.

“This tool allowed us to make several new discoveries,” explained Patel. “First, we defined the patterns of neuronal activity patterns that are required for the production of endogenous cannabinoids from the amygdala. Second, we showed that various types of stress cause increases at a specific synaptic input to the amygdala.”

Additionally, genetically removing the receptor that receives the endocannabinoid signal in mice decreased the animals’ ability to cope with stressful experiences. This was evidenced by reduced “struggle” behaviors while restrained and reduced mobility during tail suspension tests – in which mice were suspended by their tails for six minutes while connected to a force meter – and forced swim tests – in which they were placed under observation in a two-liter beaker of cold water for five minutes.

“The brain produced endogenous cannabinoid molecules when brain cells are highly active, like during stress exposure. When the receptor for these endogenous cannabinoids is removed from a specific brain connection, mice show more severe behavioral deficits after stress exposure,” added Patel.

These mice were also less likely to drink sweetened water after their stress exposure, a behavioral observation likened to anhedonia, a decrease in pleasure sometimes experienced by people affected by depression or PTSD.

Potential for treating stress-related disorders

“Using these new protein sensors to understand other situations when these endogenous cannabinoids are produced by the brain is critically important and not well understood. Understanding more about the specific types of cells that produce these molecules and cells that respond to these cannabinoids is also important,” said Patel.

Overall, the study supports the hypothesis that endogenous cannabinoids are the body’s natural coping response to stress, suggesting that the endocannabinoid system could be a promising candidate for drug development.

“If correct, that impairing the function of endogenous cannabinoids worsens the consequences of stress, perhaps increasing production of these cannabinoids could be used to treat stress-related disorders,” Patel explained. “Clinical studies remain to be completed.”

Reference: Kondev V, Najeed M, Yasmin F, et al. Endocannabinoid release at ventral hippocampal–amygdala synapses regulates stress-induced behavioral adaptation. Cell Reports. 2023. doi: 10.1016/j.celrep.2023.113027

Dr. Sachin Patel was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.