Pituitary adenylate cyclase-activating polypeptide (PACAP) in stress, pain, and learning

Abstract Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, which has been linked in both rodents and humans to stress, anxiety, and fear. PACAP signaling within the hypothalamo-pituitary-adrenocortical (HPA axis) and limbic structures mediates many of the physiological and emotional responses to chronic stress, and genetic abnormality of PAC1R signaling in humans has been linked to pathological stress and fear in post-traumatic stress disorder and major depressive disorder. PACAP modulates neuronal excitability and synaptic transmission through Gαs- and Gαq-coupled receptors and through functional interaction with glutamate receptors. In this chapter we discuss how PACAP exerts circuit- and receptor-specific modulation of anxiety, pain, aversive learning, and stress-related behavior. We also discuss sex differences in PACAP-mediated function, the link to stress disorders, and highlight the emerging data establishing the amygdala as a key site of action for PACAP.