Npbwr1signaling mediates fast antidepressant action

Abstract

AbstractChronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we reveal the receptor for neuropeptides B and W,Npbwr1, as a key regulator of depressive-like symptoms.Npbwr1is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link betweenNpbwr1, dendritic spine morphology, the biomarkerBdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist ofNpbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and altersBdnflevels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings drastically advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant.