Research Grants Program Office

Stress activates many brain nuclei and causes acute changes in several physiological and behavioral responses to restore homeostasis in affected organisms. While this response is protective, chronic stress exposure causes the sustained activation of these nuclei, leading to maladaptive physiological changes that underlie pathological mood and affective states. Hence, chronic stress may produce anxiety and mood disorders by promoting neuronal plasticity within these stress-responsive nuclei. A growing body of evidence attributes neuropeptide systems in mediating not only the physiological stress response but also pathological states that develop following chronic stress exposure. Recent preclinical data suggest that pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptors (PAC₁, VPAC₁, and VPAC₂) play an important role in the behavioral and endocrine responses to stress, as well as in mood and affective disorders. Human studies also point out the significance of the PACAP/PAC₁ receptor system in these disorders. For instance, PACAP through PAC₁ receptor up-regulates the expression of DISC1 (disrupted in schizophrenia 1) and impedes its association with its interacting protein. Interestingly, the DISC1 gene mutation is linked to schizophrenia and depression. Moreover, a link between PACAP blood titer and fear physiology, post-traumatic stress disorder (PTSD) diagnosis and symptoms has been reported in heavily traumatized female patients. Additionally, in the peripheral blood, methylation of the gene encoding the PAC₁ receptor is also associated with PTSD. This book chapter describes the emerging evidence that entails PACAP in the stress response and stress-mediated neuropsychiatric disorders.