Collaboration Results in Discovery of Possible Treatment for Post-Traumatic Stress Disorder
In a collaborative study, researchers at the Miller School led by Claes Wahlestedt, M.D., Ph.D., professor of psychiatry and behavioral sciences and Associate Dean for Therapeutic Innovation, and Shaun Brothers, Ph.D., research assistant professor, have discovered a genetic link and therapeutic strategy related to fear expression. The findings, which could have significant implications for preventing and treating Post-Traumatic Stress Disorder (PTSD), are published in the June 5 issue of Science Translational Medicine.
There are currently no approved pharmacological preventive treatments for PTSD, an anxiety disorder with altered fear learning which occurs in some individuals after exposure to a highly traumatic event.
“In our study, we demonstrate that the opioid receptor-like 1 gene (Oprl1, which encodes the nociceptin (NOP)/Orphanin FQ receptor), is involved in stress-mediated enhancement of amygdala-dependent fear in mouse models and traumatized humans with PTSD,” Wahlestedt explained. “These data follow a nascent literature in which opioid activity appears to be involved in fear inhibition and may inhibit the consolidation of fear.”
For the study, “Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD,” researchers, including Hasib Salah-Uddin, Ph.D., assistant scientist in the Department of Psychiatry and Behavioral Sciences, used a hypothesis-neutral gene discovery approach to identify a specific member of the opioid receptor population, Oprl1, which may specifically be involved in the mechanisms of this process. Using a mouse model of dysregulated fear, they found altered amygdala expression of the Oprl1 gene.
Systemic and central amygdala infusion of SR-8993, a novel and highly selective NOP receptor agonist discovered by the UM team in collaboration with former colleagues at The Scripps Research Institute, impaired fear memory consolidation. Additionally, in humans, a single nucleotide polymorphism within Oprl1 is associated with PTSD symptoms, associates with physiological startle measures of fear discrimination, and correlates with amygdala-insula functional connectivity.
Together, the data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Further, activation of the Oprl1/NOP receptor may interfere with fear memory consolidation and could prevent PTSD following trauma.
Other authors of the study include postdoctoral fellows Raül Andero Galí, Ph.D., Jennifer Stevens, Ph.D., and Lynn Almli, Ph.D.; Bekh Bradley, Ph.D., assistant professor; Elisabeth Binder, M.D., Ph.D., associate professor; Kerry Ressler, M.D., Ph.D., professor; and Tanja Jovanovic, Ph.D., assistant professor, all from the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine. Authors from The Scripps Research Institute are Youjun Chen, Ph.D., research associate; Michael Cameron, Ph.D., associate scientific director; and Thomas Bannister, Ph.D., associate scientific director.