How Normal Stress Turns Into Unchecked, Debilitating Anxiety

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PTSDResearchers at The Scripps Research Institute (TSRI) and the University of Camerino, Italy have discovered how normal stress and anxiety is transformed into a more severe form that becomes post-traumatic stress disorder (PTSD), especially when combined with a genetic predisposition to alcoholism.

“Anxiety is something that everyone experiences on a day-to-day basis,” said the study’s first author Luis A. Natividad. “But it is unclear what changes this otherwise natural process into something debilitating.”

In the new rodent study, published in the journal Biological Psychiatry, scientists discovered how two important molecules in the brain team up to cause intense anxiety.

“Anxiety and stress disorders affect millions of people worldwide,” said study leader Marisa Roberto, a professor at TSRI. “Understanding the mechanisms underlying these disorders is important for identifying potential new targets for therapeutic use.”

In the brain, there is a tug-of-war going on between cannabinoid (type 1) receptors and a peptide molecule called corticotropin-releasing factor (CRF). Cannabinoids within the body known as endocannabinoids, or eCB for short, control stress by blocking the release of brain chemicals known as neurotransmitters. While endocannabinoids reduce stress, CRF triggers the stress response and causes increased sensitivity to stress and anxiety when activated over and over again.

In the new study, the scientists investigated the relationship between the stress-promoting CRF and stress-reducing eCBs to find out how they interacted in the central nucleus of the amygdala, an important brain region involved in controlling emotional reactions. The results indicated that when overactive CRF activity in this region of the brain wins out over the stress-reducing capabilities of a major eCB called anandamide, chronic stress is transformed into unchecked, or pathological, anxiety.

The study authors looked at rats that were genetically predisposed for higher alcohol drinking and anxiety. These rats exhibit a mutation in a gene called Crhr1 that increases CRF activity. The researchers found that increased CRF activity in turn resulted in elevated activity of an enzyme called fatty acid amide hydrolase (FAAH) that clears the stress-reducing eCB anandamide from the body and stops anandamide from doing its job. Increased CRF was also linked to declines in anandamide levels in the central nucleus of the amygdala.

The researchers concluded that together, increased FAAH activity and decreased anandamide signaling reduce control of stress-related neurotransmission in this critical brain region, and weaken the brain’s ability to regulate stress and anxiety.

In later experiments, these same researchers found that inhibiting FAAH could stop CRF’s effects and lower signs of anxiety in the rats.

The researchers plan to do more experiments using this rat model in order to better understand the link between high anxiety and alcoholism as well as the connection between PTSD and the higher risk of alcoholism.

“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 Roberto Ciccocioppo, a scientist involved in the study.

Past studies have found that some dietary supplements influence CRH activity. For example, in one study, researchers investigated the effects of an omega-3 fatty acid, docosahexaenoic acid (DHA), on rats. The study authors administered CRH to the rodents. This caused the rats to become agitated and their behavior changed. However, giving the rats DHA caused stressed behaviors to stop.

In addition, in people who commit domestic violence, low plasma DHA levels are linked to higher cerebrospinal fluid CRF levels, indicating lower levels of this omega-3 fatty acid are associated with higher anxiety.

The bioflavonoid quercetin also decreases CRF expression in the brain of rodents. Researchers have found that quercetin reverses anxiety caused by CRF in mice.

Sources:

  1. McCurry-Schmidt M. Researchers Discover How the Brain Turns Chronic Stress into Pathological Anxiety. The Scripps Research Institute. News & Views. February 27, 2017;17(7). http://www.scripps.edu/newsandviews/e_20170227/roberto.html
  2. Takeuchi T, Iwanaga M, Harada E. Possible regulatory mechanism of DHA-induced anti-stress reaction in rats. Brain Res. 2003;964:136-43.
  3. Hibbeln JR, Bissette G, Umhau JC, George DT. Omega-3 status and cerebrospinal fluid corticotrophin releasing hormone in perpetrators of domestic violence. Biol Psychiatry. 2004;56:895-7.
  4. Bhutada P, Mundhada Y, Bansod K, Ubgade A, Quazi M, Umathe S, Mundhada D. Reversal by quercetin of corticotrophin releasing factor induced anxiety- and depression-like effect in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:955-60. doi: 10.1016/j.pnpbp.2010.04.025.