Npbwr1 signaling mediates fast antidepressant action

Chronic 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 identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is 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 between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant. Total mRNA sequenced 1) for 8 brain NAc (Nucleus accumbens) samples of 8 weeks old mice after stereotaxic surgery to infect NAc by empty Adeno-associated virus constructs (GFP control) and AAVs to overexpress (OE) Npbwr1. And 2) for 64 NAc samples at four time points in a 12L:12D light cycle and from two genotypes (C75BL/6J wild type and T75A-DARPP-32 mutant), 2 hours after injection with 7.5 mg/kg caffeine or saline at an injection volume of 10ml/kg body.