Specific cannabinoids produced by the human body may help to quell excessive fear responses in people with post-traumatic stress disorder and anxiety, according to a Northwestern Medicine-led study published in the Journal of Clinical Investigation.
People with post-traumatic stress disorder (PTSD) and anxiety often experience inappropriate fear responses to stimuli that may or may not be similar to those experienced during their original trauma, said Luis Rosas-Vidal, MD, PhD, assistant professor of Psychiatry and Behavioral Sciences and first author of the study.
“The endocannabinoid system – which engages the same receptors as marijuana – in your body regulates neurotransmitters release,” Rosas-Vidal said. “Specifically, the one we’re interested in, 2-AG, have been implicated in regulating fear responses and anxiety responses.”
However, if and exactly how the cannabinoid 2-AG (2-arachidonoylglycerol) functions at the neuronal level to filter fear responses when exposed to new stimuli has previously been unclear, Rosas-Vidal said.
In the study, scientists examined fear responses in mice that had depleted levels of 2-AG. They found that mice with 2-AG inhibition displayed increased fear responses. By using fiber photometry approaches, investigators found that higher fear generalization was associated with lower endocannabinoid activity in the brain.
“We found that blocking the endocannabinoid 2-AG basically leads to over-generalization of their fear responses,” said Rosas-Vidal, who is also a member of the Stephen M. Stahl Center for Psychiatric Neuroscience. The senior author of the study was Sachin Patel, MD, PhD, the chair and Lizzie Gilman Professor of Psychiatry and Behavioral Sciences.
In collaboration with investigators at University of Calgary and Linköping University, the investigators observed how 2-AG levels in blood relate to fear generalization in human research participants. Similarly, they found that lower 2-AG levels were associated with higher fear generalization.
Together, the findings highlight the key role endocannabinoids play in regulating fear responses, Rosas-Vidal said, and identify 2-AG as a potential target for anxiety therapies.
“We think that our findings are really exciting,” he said. “They show both at the mechanistic and behavioral level how 2-AG is regulating fear responses.”
Moving forward, Rosas-Vidal and his collaborators will continue to study cannabinoid signaling in different neuron subtypes and the mechanisms mediating generalization, he said.
“We believe these sorts of studies are very vital in psychiatry to give us understanding of how psychiatric disorders arise and also point to potential treatments in the future,” he said.
The study was supported by the National Institute of Mental Health grants K08MH126166 and R01MH107435. Additional funding was provided by the Brain and Behavior Research Foundation’s Young Investigator Grant 29255.
