High blood levels of a stress hormone called PACAP may explain why women but not men have a much higher risk of developing post-traumatic stress disorder (PTSD), according to a new US study published online in Nature this week.

The researchers, from Emory University and the University of Vermont, also found that women with a certain “protective” variation of the gene that codes for the PACAP hormone’s receptor had a lower rate of PTSD than men, even though they had experienced similar levels of trauma.

The identification of PACAP (short for pituitary adenylate cyclase-activating polypeptide), as an indicator of PTSD could lead to new ways of diagnosing, and one day treating, anxiety disorders.

First author Dr Kerry Ressler, associate professor of psychiatry and behavioral sciences at Emory University School of Medicine in Atlanta, told the press their findings reveal a “new window” into the biology of PTSD.

“Few biological markers have been available for PTSD or for psychiatric diseases in general,” said Ressler, who is also a researcher at the Yerkes National Primate Research Center.

We already know that PACAP broadly regulates the stress response at the cellular level: it acts throughout the body and the brain, influencing the central nervous system, immune function, blood pressure, metabolism, and sensitivity to pain.

But, as the authors wrote in their background information, it is not clear if the biological pathway that PACAP operates with its receptor, PAC1, has a role in human psychological stress responses, such as PTSD.

For their study, Ressler and colleagues, used data from the Grady Trauma Project, which included more than 1,200 low-income residents of Atlanta who experienced high levels of violence, physical and sexual abuse, resulting in high rates of PTSD for a civilian population.

Ressler, who is also a Howard Hughes Medical Institute Investigator, co-directs the Project with co-author Dr Bekh Bradley, an assistant professor of psychiatry and behavioral sciences at Emory and director of the Trauma Recovery Program at the Atlanta Veterans Affairs Medical Center.

The participants were patients who were attending the Grady Memorial Hospital in Atlanta. Starting in 2005, the researchers interviewed them in waiting rooms in the hospital’s various primary care, ob-gyn and other clinics, and asked them to complete questionnaires about their life history, and give samples of blood and saliva.

The data showed that women, but not men, with high blood levels of PACAP showed more PTSD symptoms, such as finding it difficult to tell the difference between fear and safety signals, and being easily startled.

In a group of 64 people, where most of them had been through significant traumatic events, women who had above average blood levels of PACAP had PTSD symptom scores five times those of women whose PACAP levels were below average.

The researchers also found that a variation in the gene for PACAP’s receptor PAC1, which may affect how the gene responds to estrogen, was also linked to PTSD diagnosis and symptoms in women only.

But, Ressler pointed out, among men and women who had experienced similar levels of trauma, they found that women with a more protective variation of the PAC1 gene had lower PTSD rates than men, while those with the variation that conferred higher risk, had higher rates of PTSD than men.

“What this says is that men and women who have been traumatized may arrive at PTSD by different biological pathways,” said Ressler.

“In this case, we have a clue how that works, in that the genetic data point to changes in the ability to respond to estrogen,” he added.

One of his co-authors, Dr Sayamwong “Jom” Hammack, was previously a postdoctoral fellow at Yerkes National Primate Research Center, and is now Assistant Professor of Psychology at the University of Vermont, where in previous experiments with rats, they found that under stress, PACAP increases ten-fold in a part of the brain called the BNST (bed nucleus of the stria terminalis), which is thought to be important for anxiety behavior.

Hammack said that:

“In the brain, PACAP can activate brain cells, and it is also neurotrophic, helping brain cells survive, grow and form connections.”

“In many brain areas, this is great, but in others, such as those involved in sustained anxiety behavior, this might not be so good,” he added.

The researchers hope that more studies like this will help diagnose PTSD and similar anxiety disorders separately from other behavioral disorders, and perhaps even help identify which people in high stressed jobs and work environments might be more prone to developing PTSD.

Note that this study relied on samples collected after PTSD developed, and some experts might want to know how many of the physiological effects were already there before the trauma, and if so, how this might influence the results.

Ressler said it was important to see if the same findings occur in other groups, including veterans with PTSD.

Also, it would be useful to find out if PACAP increases in the brain and blood as PTSD develops, as this would help establish if drugs that act against it might help.

“Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.”
Kerry J. Ressler, Kristina B. Mercer, Bekh Bradley, Tanja Jovanovic, Amy Mahan, Kimberly Kerley, Seth D. Norrholm, Varun Kilaru, Alicia K. Smith, Amanda J. Myers, et al.
Nature 470, 492-497, published online 23 February 2011.

Additional source: Emory University (press release, 23 Feb 2011).

Written by: Catharine Paddock, PhD