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

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 Engel, Sayamwong E. Hammack, Donna Toufexis, Karen M. Braas, Elisabeth B. Binder, Victor May

Research output: Contribution to journalArticle

422 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)492-497
Number of pages6
JournalNature
Volume470
Issue number7335
DOIs
StatePublished - Feb 24 2011

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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
Pituitary Adenylate Cyclase-Activating Polypeptide Receptors
Post-Traumatic Stress Disorders
Pituitary Adenylate Cyclase-Activating Polypeptide
Single Nucleotide Polymorphism
Fear
Estrogens
Messenger RNA
Estrogen Replacement Therapy
Response Elements
Psychological Stress
Methylation
Rodentia
Biomarkers

ASJC Scopus subject areas

  • General

Cite this

Ressler, K. J., Mercer, K. B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., ... May, V. (2011). Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature, 470(7335), 492-497. https://doi.org/10.1038/nature09856

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

In: Nature, Vol. 470, No. 7335, 24.02.2011, p. 492-497.

Research output: Contribution to journalArticle

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 2011, 'Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor', Nature, vol. 470, no. 7335, pp. 492-497. https://doi.org/10.1038/nature09856
Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature. 2011 Feb 24;470(7335):492-497. https://doi.org/10.1038/nature09856
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. / Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. In: Nature. 2011 ; Vol. 470, No. 7335. pp. 492-497.
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