Luzhou‐Flavor Baijiu Alleviates Stress‐Related Depressive‐Like Changes by NMDAR‐NO‐sGC‐cGMP Pathway

ABSTRACT Moderate alcohol consumption has been suggested to alleviate anxiety and depression; however, it remains unclear whether Luzhou‐flavor baijiu (LFB) exerts similar effects and what underlying mechanisms may be involved. To investigate this, we established a chronic restraint stress (CRS)‐induced depression model in C57BL/6 mice (in vivo) and a corticosterone‐induced depressive‐like cell injury model in HT22 hippocampal neurons (in vitro). Behavioral assessments revealed that LFB significantly ameliorated depressive‐like behaviors in CRS‐exposed mice. Biochemical analyses indicated that LFB reduced Tyr1474 phosphorylation of the GluN2B subunit of N ‐methyl‐D‐aspartate receptors (NMDARs) and downregulated the downstream NMDAR cascade, specifically, by suppressing neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) gene expression, reducing nitric oxide (NO) production, attenuating soluble guanylate cyclase (sGC) activity, and decreasing cyclic guanosine monophosphate (cGMP) levels. These findings suggest that LFB exerts protective effects against CRS‐induced depressive phenotypes, likely by modulating the NMDAR‐nNOS/iNOS‐NO‐sGC‐cGMP signaling pathway. This provides a mechanistic basis for understanding its potential role in depression‐related conditions.