title: Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD.
abstract: The amygdala-dependent molecular mechanisms driving the onset and persistence of posttraumatic stress disorder (PTSD) are poorly understood. Recent observational studies have suggested that opioid analgesia in the aftermath of trauma may decrease the development of PTSD. Using a mouse model of dysregulated fear, we found altered expression within the amygdala of the Oprl1 gene (opioid receptor-like 1), which encodes the amygdala nociceptin (NOP)/orphanin FQ receptor (NOP-R). Systemic and central amygdala infusion of SR-8993, a new highly selective NOP-R agonist, impaired fear memory consolidation. In humans, a single-nucleotide polymorphism (SNP) within OPRL1 is associated with a self-reported history of childhood trauma and PTSD symptoms (n = 1847) after a traumatic event. This SNP is also associated with physiological startle measures of fear discrimination and magnetic resonance imaging analysis of amygdala-insula functional connectivity. Together, these data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Further, our data suggest that activation of the Oprl1/NOP receptor may interfere with fear memory consolidation, with implications for prevention of PTSD after a traumatic event.
authors.affiliation: Yerkes National Primate Research Center, Atlanta, GA 30329, USA.
authors.forename: Raül
authors.initials: R
authors.lastname: Andero
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Brothers
authors.forename: Tanja
authors.initials: T
authors.lastname: Jovanovic
authors.forename: Yen T
authors.initials: YT
authors.lastname: Chen
authors.forename: Hasib
authors.initials: H
authors.lastname: Salah-Uddin
authors.forename: Michael
authors.initials: M
authors.lastname: Cameron
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bannister
authors.forename: Lynn
authors.initials: L
authors.lastname: Almli
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Stevens
authors.forename: Bekh
authors.initials: B
authors.lastname: Bradley
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
mesh_terms: D000328:Adult; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000187:drug effects; D003463:Cues; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007103:Immobilization; D008297:Male; D008569:Memory Disorders / Q000378:metabolism / Q000503:physiopathology; D057567:Memory, Long-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism* / Q000503:physiopathology; D000094942:Nociceptin Receptor
chemical_list: D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor