Dentate nNOS accounts for stress‐induced 5‐HT 1A receptor deficiency: Implication in anxiety behaviors

Background Anxiety is a common disorder with high social burden worldwide. Dysfunction of serotonin‐ 1A receptor (5‐HT 1A receptor) in the dentate gyrus (DG) of the hippocampus has been predominantly implicated in the anxiety behavior. However, the molecular mechanism underlying the deficiency of postsynaptic 5‐HT 1A receptor in regulating anxiety behavior remains unclear. Methods Using pharmacological and genetic methods, we investigated the role of detate nNOS in 5‐HT 1A receptor decline and anxiety behavior induced by chronic mild stress (CMS) in mice. Results Here we showed that local elevation of glucocorticoids in the DG accounted for chronic stress‐induced anxiety behavior. Neuronal nitric oxide synthase (nNOS) mediated chronic stress‐induced downregulation of 5‐HT 1A receptor in the DG through peroxynitrite anion (ONOO•) pathway but not cyclic guanosine monophosphate (cGMP) pathway. By using pharmacological tool drugs and nNOS knockout mice, we found that nNOS in the DG played a key role in chronic stress‐induced anxiety behavior. Conclusions These findings uncovered an important role of nNOS‐5‐HT 1A receptor pathway in the DG of the hippocampus in chronic stress‐induced anxiety. Accordingly, we developed a “dentate nNOS‐5‐HT 1A receptor closed‐loop” theory (stress‐glucocorticoids‐nNOS‐Nitric oxide‐ONOO•‐5‐HT 1A receptor ‐nNOS) of stress‐related anxiety.