Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor

By K. Ressler, Kristina B. Mercer, B. Bradley, T. Jovanović, A. Mahan, Kimberly Kerley, S. Norrholm, V. Kilaru, Alicia K. Smith, A. Myers and 7 more. Nature, 2011

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Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP–PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP–PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.

Subfields: Behavioral Neuroscience, Cellular and Molecular Neuroscience, Social Psychology

View Paper: https://www.semanticscholar.org/paper/3d60aadc0d0400f05a12117f1e7fb5f1684ac494

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Citations in the corpus

Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress (2012, background): “[PubMed: 1151290] Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.”
Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect. (2016, background): “…2013) in mediating risk for depression and anxiety, the adrenergic b-2 receptor polymorphism for PTSD (Liberzon et al., 2014), the PAC1 receptor (Ressler et al., 2011), and the opioid receptor-like 1 receptor (Andero et al., 2013) for PTSD and themethylenetetrahydrofolate reductase (MTHFR)…”
Sex differences in anxiety and depression clinical perspectives (2014, background): “In addition, blood levels of PACAP, a neuropeptide involved in coordinating the brain’s response to stress and a polymorphism in the gene that encodes PACAP’s receptor PAC1, are both associated with increased risk for PTSD in women, but not in men (Ressler et al., 2011).”