A Novel PACAP receptor PAC1 antagonist exhibits fast and lasting anti-depressant effect

Psychiatric disorders, such as depression and anxiety related disorders, posed a significant burden worldwide. Therefore, it is necessary to develop additional safe and effective antidepressants. Accumulating evidence indicates that PACAP (pituitary adenylate cyclase-activating polypeptide) and its preferring receptor PAC1 are involved in psychiatric disorders, especially stress-related disorders. Recently, we developed novel small-molecule, non-peptide, and high-affinity PAC1 antagonists and showed that the antagonists significantly attenuated mechanical allodynia in mice. In this study, we aimed to characterize the PAC1 antagonist as a new therapeutic reagent for stress-related disorders and conducted behavioral pharmacological experiments in mice. A single dose of the PAC1 antagonist significantly improved anxiety-like and depressive-like behaviors in chronic social defeated stress mice, and this effect lasted long period which was similar to that of ketamine. In addition, the PAC1 antagonist did not exhibit behavioral impairments, including pre-pulse inhibition deficits and cognitive deficits in naïve control mice. These results indicate that the novel PAC1 antagonist may have a robust antidepressant effect and highly safe profile.