EMORY (US) — A new compound reduces PTSD-like symptoms in mice that have been exposed to stress, a finding that could lead to a treatment given to people shortly after a traumatic event.
The research meshes with recent studies—including one looking at military personnel injured in Iraq—hinting that morphine administered after traumatic injury may lower the risk of developing post-traumatic stress disorder.
“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, professor of psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.
The compound, 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 the University of Miami and Scripps Research Institute 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, specifically 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.
Fear memory consolidation
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.
The discovery led Ressler to contact co-author Claes Wahlestedt, professor of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine, who had been investigating Oprl1’s role in the brain, but had focused on addiction rather than PTSD.
As reported in the journal Science Translational 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.
The researchers 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. The compound does 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.
The National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the National Center for Advancing Translational Sciences, NARSAD, the Burroughs Wellcome Fund, and Emory Medical Care Foundation supported the research.
Source: Emory University