A cannabinoid our bodies produce naturally has been found, in a new study, to play a role in the inappropriate regulation of fear responses characteristic of conditions like anxiety and PTSD. The discovery opens the door to developing a treatment that targets this specific chemical.
People with post-traumatic stress disorder (PTSD) and anxiety often experience an exaggerated fear response that can be triggered by reminders of the traumatic event. Fear generalization occurs when that fear response is inappropriately extended to other stimuli beyond the original threat, leading to avoidance behaviors, social isolation, and difficulty functioning in daily life.
A new study led by researchers at Northwestern University’s Feinberg School of Medicine (Northwestern Medicine) has discovered that a specific naturally occurring messenger, a cannabinoid called 2-arachidonoylglycerol or 2-AG, contributes to maladaptive fear generalization.
“The endocannabinoid system – which engages the same receptors as marijuana – in your body regulates neurotransmitters release,” said lead author Luis Rosas-Vidal, MD, PhD, assistant professor in Northwestern’s Department of Psychiatry and Behavioral Sciences. “Specifically, the one we’re interested in, 2-AG, have been implicated in regulating fear responses and anxiety responses.”
As Rosas-Vidal hinted at, endogenous cannabinoids or endocannabinoids are produced by the body to activate CB1 (cannabinoid receptor 1) receptors, the receptors that are also responsible for producing the psychoactive effects of cannabis. 2-AG is one such endocannabinoid. Previous studies had found that 2-AG modulated fear, anxiety and stress, but its role in fear generalization, also called over-generalization of fear, wasn’t clear.
So, to gain a better understanding of 2-AG’s role in fear generalization, the researchers first studied mice with lowered levels of 2-AG. They observed that the animals' fear responses were increased. In humans, they found that blood levels of 2-AG were inversely correlated with fear generalization. As was seen with the mice, lower 2-AG levels were associated with higher fear generalization.
“We found that blocking the endocannabinoid 2-AG basically leads to over-generalization of their fear responses,” Rosas-Vidal said.
The findings open the door to developing a treatment for anxiety by targeting 2-AG. The researchers will continue to study cannabinoid signaling in different neuron types and how that impacts fear responses.
“We think our findings are really exciting,” said Rosas-Vidal. “They show both at the mechanistic and behavioral level how 2-AG is regulating fear responses. 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.”
Interestingly, another recently published study led by Indiana University (IU) reported that acetaminophen (also known as paracetamol) decreased 2-AG production in mice, which may go some way to explaining the drug’s mysterious pain-relieving properties.
“There are hypotheses, but we still don’t know precisely how it works,” said the study’s lead author, Michaela Dvorakova, PhD, a postdoctoral researcher at IU’s Gill Institute for Neuroscience. “Up until now we though that elevated endocannabinoids in our body meant less pain, but our study shows that in the case of 2-AG, it might be the opposite. Actually, reduced levels of 2-AG leads to decreased pain.”
The Northwestern-led study examining the relationship between 2-AG and fear generalization was published in The Journal of Clinical Investigation.
Source: Northwestern Medicine
