Anxiety and stress disorders affect millions of people worldwide. In a new study, researchers at The Scripps Research Institute (TSRI)
have described how two important molecules in the brain work together to
trigger intense anxiety.
The new findings in animal models point to a novel interaction in
the regulation of the brain's stress response that may underlie the
pathological anxiety related to symptoms of post-traumatic stress
‘An overactive CRF signaling in the central nucleus of the amygdala, produces a wide range of effects that override the stress-reducing capabilities of a major endocannabinoid called anandamide, turning chronic stress into unchecked, or pathological, anxiety.’
Study leader Marisa Roberto, a professor at TSRI, said,
"Understanding the mechanisms underlying these disorders is important
for identifying potential new targets for therapeutic use."
The researchers focused on the endogenous cannabinoid
(endocannabinoid or eCB) system, which include natural lipid signaling
molecules that bind to cannabinoid receptors in the brain. Cannabinoid
(type 1) receptors control stress-mediating circuits by inhibiting
neurotransmitter release - a sort of gating mechanism to keep anxiety
In contrast to the stress-reducing properties of endocannabinoids, a
peptide molecule called corticotropin-releasing factor (CRF) activates
the stress response and promotes increased sensitivity to stress and
anxiety when activated over and over again.
In the new study, published today in the journal Biological Psychiatry
the researchers investigated the interaction between the
stress-promoting (CRF) and stress-constraining (eCBs) mechanisms in the
central nucleus of the amygdala, a critical brain region involved in
mediating emotional reactions. The findings suggest that overactive CRF
signaling in this region produces a wide range of effects that override
the stress-reducing capabilities of a major eCB called
N-arachidonoylethanolamine (anandamide), turning chronic stress into
unchecked, or pathological, anxiety.
"Anxiety is something that everyone experiences on a day-to-day
basis," said study first author Luis A. Natividad, a research associate
in the Roberto lab. "But it is unclear what changes this otherwise
natural process into something debilitating."
To answer this question, Roberto's lab teamed up with Roberto
Ciccocioppo's lab at the University of Camerino, Italy, and the lab of
TSRI Professor Loren ("Larry") Parsons, a renowned leader in the fields
of endocannabinoid signaling, stress and drug addiction who passed away
The researchers studied rats that were genetically selected for
higher alcohol drinking and also display an anxiety-like phenotype.
These rats exhibit a mutation in a gene called Crhr1 that increases CRF
(type 1) receptor signaling.
Using behavioral, neurochemical and electrophysiological approaches,
the researchers found that increased CRF signaling led to elevated
activity of the anandamide clearance enzyme fatty acid amide hydrolase
(FAAH). Increased CRF was also associated with drops in anandamide
levels in the central nucleus of the amygdala. Together, increased FAAH
activity and decreased anandamide signaling reduce inhibitory control of
excitatory neurotransmission in this critical region, and lower the
brain's ability to regulate stress and anxiety.
The researchers concluded that long-term dysregulation of CRF-FAAH
mechanisms in the amygdala keeps anandamide from doing its job. Without
anandamide to balance out the system, the brain is primed to react to
Follow-up experiments showed that inhibiting FAAH could blunt CRF's effects and reduce signs of anxiety in the rats.
Roberto said the next step will be to further study this rat model
to better understand relationships between high anxiety and alcoholism.
She added that the rat model could also be useful for studying PTSD,
where high anxiety is connected to a higher risk of developing
"The results of our study may be useful, not only in understanding
the neurobiological basis of alcoholism, anxiety and possibly PTSD, but
also in developing more efficacious pharmacotherapies to treat these
disorders," added Ciccocioppo.
The researchers dedicated this study to Parsons. Natividad added a
note on Parson's influence on the research and on the TSRI campus:
"Larry's guidance throughout the study was critical in bringing
together a cohesive story exploring the relevance of endocannabinoid
signaling with downstream neural processing in a way that is unique to
the field and has translational relevance to the human condition. He
serves as a role model for me not only as a scientist, but also in terms
of being a good colleague, mentor and friend to those around him. I
feel privileged to have been part of his lab, his teachings and
mentorship. He will be dearly missed."