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

Author

Listed:
  • Kerry J. Ressler

    (Howard Hughes Medical Institute
    Emory University School of Medicine
    Yerkes National Primate Research Center)

  • Kristina B. Mercer

    (Howard Hughes Medical Institute)

  • Bekh Bradley

    (Emory University School of Medicine
    Atlanta VA Medical Center)

  • Tanja Jovanovic

    (Emory University School of Medicine)

  • Amy Mahan

    (Yerkes National Primate Research Center)

  • Kimberly Kerley

    (Howard Hughes Medical Institute)

  • Seth D. Norrholm

    (Emory University School of Medicine
    Atlanta VA Medical Center)

  • Varun Kilaru

    (Emory University School of Medicine)

  • Alicia K. Smith

    (Emory University School of Medicine)

  • Amanda J. Myers

    (University of Miami, Miller School of Medicine)

  • Manuel Ramirez

    (University of Miami, Miller School of Medicine)

  • Anzhelika Engel

    (University of Miami, Miller School of Medicine)

  • Sayamwong E. Hammack

    (University of Vermont)

  • Donna Toufexis

    (Yerkes National Primate Research Center
    University of Vermont)

  • Karen M. Braas

    (University of Vermont College of Medicine)

  • Elisabeth B. Binder

    (Emory University School of Medicine
    Max Planck Institute of Psychiatry)

  • Victor May

    (University of Vermont College of Medicine)

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.

Suggested Citation

  • Kerry J. Ressler & Kristina B. Mercer & Bekh Bradley & Tanja Jovanovic & Amy Mahan & Kimberly Kerley & Seth D. Norrholm & Varun Kilaru & Alicia K. Smith & Amanda J. Myers & Manuel Ramirez & Anzhelika , 2011. "Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor," Nature, Nature, vol. 470(7335), pages 492-497, February.
    • Handle: RePEc:nat:nature:v:470:y:2011:i:7335:d:10.1038_nature09856
    DOI: 10.1038/nature09856
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    Cited by:

    1. Devin Rocks & Mamta Shukla & Laila Ouldibbat & Silvia C. Finnemann & Achyuth Kalluchi & M. Jordan Rowley & Marija Kundakovic, 2022. "Sex-specific multi-level 3D genome dynamics in the mouse brain," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Takashi Nagashima & Suguru Tohyama & Kaori Mikami & Masashi Nagase & Mieko Morishima & Atsushi Kasai & Hitoshi Hashimoto & Ayako M. Watabe, 2022. "Parabrachial-to-parasubthalamic nucleus pathway mediates fear-induced suppression of feeding in male mice," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. E. R. Velasco & A. Florido & Á Flores & E. Senabre & A. Gomez-Gomez & A. Torres & A. Roca & S. Norrholm & E. L. Newman & P. Das & R. A. Ross & A. Lori & O. J. Pozo & K. J. Ressler & L. L. Garcia-Estev, 2022. "PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Morgan Heinzelmann & Jessica Gill, 2013. "Epigenetic Mechanisms Shape the Biological Response to Trauma and Risk for PTSD: A Critical Review," Nursing Research and Practice, Hindawi, vol. 2013, pages 1-10, April.

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