Fear learning studies point to a potential new treatment for PTSD

(Press-News.org) A team of researchers from Emory, University of Miami and Scripps Research Institute has identified a compound that can reduce PTSD-like symptoms in mice after they are exposed to stress. The discovery could lead to a treatment given to people shortly after a traumatic event, aimed at preventing possible PTSD (post-traumatic stress disorder).

The results are scheduled for publication Wednesday in the journal Science Translational Medicine.

The team's research meshes with recent studies – one looking at military personnel injured in Iraq -- hinting that morphine administration after traumatic injury may lower the risk of developing PTSD.

"At first glance, one might infer that the main mechanism by which morphine is working is through pain reduction, but our results lead us to think it could also be affecting the process of fear learning," says senior author Kerry Ressler, MD, PhD, professor of psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

The compound his team tested, called SR-8993, hits one, but not all, of several molecular buttons in the brain pushed by opioid drugs such as morphine and oxycodone. SR-8993 was developed by scientists at Miami and Scripps to potentially treat alcohol and drug addiction and does not appear to have narcotic or addictive effects.

"We hypothesized that the fear and anxiety component of addiction relapse may be related, in terms of brain chemistry, to the anxiety felt by PTSD patients," says co-author Thomas Bannister, PhD, associate director of translational research and assistant professor of medicinal chemistry at Scripps Research Institute in Florida.

Ressler says his laboratory didn't set out to examine the effects of opioid drugs in the context of PTSD. Rather, he and postdoctoral fellow Raul Andero were looking at what genes are activated in the brains of mice after they are exposed to stress. They were specifically probing for changes in the amygdala, a region of the brain long known to be involved in regulating fear responses. Mice exposed to stress (physical immobilization) become more anxious and tend to freeze in fear, even when there is no "danger" signal.

"This behavior models some aspects of PTSD in humans," Andero says.

He and Ressler found that exposure to stress particularly affects regulation of the gene Oprl1 (opioid receptor-like 1) in the amygdala. While mice are learning to become afraid of a sound paired with a mild electric shock, Oprl1 normally becomes turned off. But when the mice were previously exposed to stress, the gene stays on, Andero observed.

The discovery led Ressler to contact co-author Claes Wahlestedt, MD, PhD, who had been investigating Oprl1's role in the brain with Bannister, but focused on addiction rather than PTSD. Wahlestedt is associate dean for therapeutic innovation and professor of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine.

The protein encoded by Oprl1 is part of a family of opioid receptors, which allow brain cells to receive signals from opioid drugs as well as natural compounds produced by the body. Scientists believe the euphoric and analgesic effects of opioid drugs mainly come by triggering other members of the opioid receptor family, not Oprl1. Mice lacking the Oprl1 gene are actually more sensitive to the reward effects of morphine.

Wahlestedt and Bannister had developed SR-8993 as a compound that activates Oprl1 more than other opioid receptors, thus avoiding narcotic and addictive effects. When Andero gave SR-8993 to mice, it impaired "fear memory consolidation." That is, mice could still learn to become afraid of sounds and shocks, but the fearful memories were not as durable and the mice did not freeze as much in response to the sound alone two days later, even if they had been previously exposed to stress. SR-8993 did not seem to affect sensitivity to pain.

"We think SR-8993 is helping to promote a natural process that occurs after trauma, preventing fear learning from becoming over-represented and generalized," Ressler says. "Our model is that in PTSD, the Oprl1 system is serving as a brake on fear learning, but that brake is not working if prior trauma had occurred."

Bolstering the experiments with animals, Ressler and his colleagues found that people with a variation in the Oprl1 gene who experienced childhood abuse tend to have stronger PTSD symptoms. They also have more difficulty discriminating between "danger" and "safety" signals in experiments when they hear startling noises. This data came from the Grady Trauma Project, a study of people in inner-city Atlanta exposed to high rates of violence and sexual and physical abuse.

"While many hurdles remain for SR-8993 or a related compound to become a drug used to prevent PTSD, these results are important first steps in understanding how such treatments may be effective," Bannister says.

### Reference: R. Andero et al. Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Trans Med (2013)