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.

慢性压力是抑郁症的主要危险因素，是导致残疾和自杀的主要原因。由于目前的抗抑郁药起效缓慢，具有常见的副作用，并且仅对少数患者有效，因此需要确定潜在的分子机制。在这里，我们确定了神经肽 B 和 W 的受体 Npbwr1 是抑郁样症状的关键调节因子。Npbwr1 在慢性应激小鼠的伏隔核和诊断为抑郁症的患者的死后增加。使用病毒介导的基因转移，我们证明了 Npbwr1、树突状脊柱形态、生物标志物 Bdnf 和抑郁样行为之间的因果关系。重要的是，显微注射 Npbwr1 的合成拮抗剂 CYM50769 可迅速改善抑郁样行为症状并改变 Bdnf 水平。CYM50769 具有选择性，耐受性好，并且在单次给药后长达 7 天显示出效果。总之，这些发现促进了我们对情绪和慢性压力的理解，并需要进一步研究 CYM50769 作为一种潜在的速效抗抑郁药。