Cited by 800Posttraumatic Stress Disorder ResearchNeuropeptides and Animal PhysiologyStress Responses and Cortisol

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

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Ressler, Kerry J., Mercer, Kristina B., Bradley, Bekh, Jovanovic, Tanja, Mahan, Amy, Kerley, Kimberly, Norrholm, Seth D., Kilaru, Varun, Smith, Alicia K., Myers, Amanda J., Ramirez, Manuel, Engel, Anzhelika, Hammack, Sayamwong E., Toufexis, Donna, Braas, Karen M., Binder, Elisabeth B., May, Victor·2011·Nature

DOI 10.1038/nature09856PMC PMC3046811

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Abstract

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.

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Authors: Ressler, K. J., Mercer, K. B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S. D., Kilaru, V., Smith, A. K., Myers, A. J., Ramirez, M., Engel, A., Hammack, S. E., Toufexis, D., Braas, K. M., Binder, E. B., & May, V.
Affiliations: Howard Hughes Medical Institute (US)
Emory University (US)
Emory National Primate Research Center (US)
University of Miami (US)
University of Vermont (US)
Corresponding author: Ressler, Kerry J.
ORCID: Ressler, Kerry J.
Bradley, Bekh
Norrholm, Seth D.
Kilaru, Varun
Smith, Alicia K.
Myers, Amanda J.
Hammack, Sayamwong E.
Toufexis, Donna
Binder, Elisabeth B.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-02-23
Volume: 470
Issue: 7335
Pages: 492-497
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature09856
PMC: PMC3046811
OpenAlex: W2068480672
Cited by: 800
References: 42
Citations by year: 2026: 27 · 2025: 31 · 2024: 35 · 2023: 39 · 2022: 45 · 2021: 66 · 2020: 53 · 2019: 42 · 2018: 55 · 2017: 57 · 2016: 76 · 2015: 57 · 2014: 63 · 2013: 64 · 2012: 58
FWCI: 74.73
Type: journal article
Language: en
Update notices: addendum (2011-08-31)
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Max Planck Institute for Plasma Physics (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health (UL1TR000454)
National Institute on Aging (AG-034504, R01AG034504)
National Institute of Mental Health (MH 071537, R01MH071537, R56MH071537)
National Institute on Drug Abuse (R01DA019624, DA-019624)
National Center for Research Resources (M01-RR00039, P20-RR16435, P20RR016435, M01RR000039)
National Center for Advancing Translational Sciences
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-27468, R01HD027468)
Topics: Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: post-traumatic stress disorder, PACAP, PAC1 receptor, ADCYAP1, ADCYAP1R1, sex differences, fear conditioning, estrogen response element, single nucleotide polymorphisms, DNA methylation, biomarkers, amygdala, stress response, estrogen replacement therapy
MeSH terms: Amygdala, Animals, Conditioning, Classical, Estrogens, Fear, Female, Gene Expression Regulation, Humans, Male, RNA, Messenger, Septal Nuclei, Sex Characteristics, Stress Disorders, Post-Traumatic, CpG Islands, DNA Methylation, Genetic Predisposition to Disease, Response Elements, Polymorphism, Single Nucleotide, Pituitary Adenylate Cyclase-Activating Polypeptide, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I, Mice, Rats, Genetic Association Studies

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

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