Targeting PACAP Receptors: A Potential New Treatment for Stress-related disorders, including depression

Hitoshi HASHIMOTO
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences

Atsuko HAYATA
Department of Pharmacology, Graduate School of Dentistry

Researchers from the University of Osaka, University of Toyama, Hiroshima University, and Kagoshima University have collaborated to demonstrate that a novel small-molecule, non-peptide, high-affinity antagonist of the PAC1 receptor, a specific receptor for the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), exhibits rapid and long-lasting antidepressant effects in animal models of depression after a single administration.

The lifetime prevalence of depression in Japan is estimated to be approximately 7%, which represents a significant societal burden. Individuals experiencing stressful life events are at increased risk of developing depression. Current pharmacological treatments for depression often require several weeks to take effect, and some patients exhibit treatment resistance, highlighting the need for safe and fast-acting antidepressants.

In this study, administration of PA-915 rapidly improved anxiety-like behavior, depression-like behavior, and cognitive impairment in chronic stress-induced mouse models of depression. Furthermore, an antidepressant-like effect was observed for 8 weeks in mice that received a single dose of PA-915 in the sucrose preference test. The researchers also observed an improvement in the reduced dendritic spine density in the medial prefrontal cortex (mPFC), suggesting enhanced neuronal function.

Remarkably, PA-915 did not induce behavioral abnormalities in non-stressed mice. This suggests a different mechanism of action compared to existing antidepressants and raises expectations for a high safety profile.

Our findings represent a potential breakthrough in the development of novel antidepressants and offer hope for the development of safe, rapid, and long-lasting pharmacological treatments for depression.

This article, “Rapid and long-lasting antidepressant-like effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models” was published online in the American scientific journal Molecular Psychiatry on September 4th (Japan Standard Time) at DOI： https://doi.org/10.1038/s41380-025-03209-4