The neuropeptide PACAP is found in neurons of the prefrontal cortex, hippocampus, thalamus, hypothalamus, and brainstem. PACAP-38 and the truncated PACAP-27 are produced via cleavage of the 176 amino acid precursor (prepro-PACAP). These peptides act at class B G protein-coupled receptors (GPCRs); PAC1 receptor (PAC1R) is the PACAP selective receptor, binding PACAP with an affinity 1000-fold greater compared to the vasoactive intestinal peptide (VIP). PACAP neurons send widespread projections to regions of the brain that regulate arousal and behavioral states, including the nucleus accumbens and the extended amygdala. The PACAP system is recognized as a key master regulator of the stress response as it regulates the autonomic, endocrine, as well as behavioral response to stress. Notably, the brain PACAP system, recruited after exposure to stress, stays active when the stressor persists, and mediates the detrimental effects of chronic stress. Evidence indicates that the PACAP system is dysregulation in specific neural circuits in several stress-related and trauma-related disorders, but also in addiction. Here, we will review evidence that PACAP is implicated in the pathophysiology of several psychiatric disorders by reviewing current preclinical and clinical evidence, with a focus on the brain regions and circuits where the dysregulated PACAP signaling may mediate the abnormal behaviors. The data available suggest that blocking PAC1R would have beneficial effects and warrant the further investigation of the topic, with the ultimate goal of developing small molecule antagonists for PAC1R for the treatment of stress-related disorders, PTSD, and addiction. / 2025-02-01T00:00:00Z

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.