Pituitary Adenylate Cyclase Activating Polypeptide (PACAP), Stress, and Sex Hormones

Stress. 2017 Sep;20(5):465-475. doi: 10.1080/10253890.2017.1336535. Epub 2017 Jun 14.


Stressor exposure is associated with the onset and severity of many psychopathologies that are more common in women than men. Moreover, the maladaptive expression and function of stress-related hormones have been implicated in these disorders. Evidence suggests that PACAP has a critical role in the stress circuits mediating stress-responding, and PACAP may interact with sex hormones to contribute to sex differences in stress-related disease. In this review, we describe the role of the PACAP/PAC1 system in stress biology, focusing on the role of stress-induced alterations in PACAP expression and signaling in the development of stress-induced behavioral change. Additionally, we present more recent data suggesting potential interactions between stress, PACAP, and circulating estradiol in pathological states, including PTSD. These studies suggest that the level of stress and circulating gonadal hormones may differentially regulate the PACAPergic system in males and females to influence anxiety-like behavior and may be one mechanism underlying the discrepancies in human psychiatric disorders.

Keywords: Estrogen; PAC1; PTSD; anxiety; bed nucleus of the stria terminalis; sex difference.

Publication types

  • Review

MeSH terms

  • Animals
  • Anxiety / metabolism*
  • Estradiol / metabolism*
  • Female
  • Gonadal Steroid Hormones / metabolism
  • Humans
  • Male
  • Mice
  • Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism*
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / metabolism*
  • Septal Nuclei / metabolism*
  • Sex Characteristics
  • Sex Factors
  • Stress Disorders, Post-Traumatic / metabolism*
  • Stress, Psychological / metabolism*


  • Adcyap1r1 protein, mouse
  • Gonadal Steroid Hormones
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
  • Estradiol