Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine
Huoqing Luo, Ming Chen, Yingjie Ning, Li Ren, Yiping Lu, Junyou Sun, Xiaona Zhu, Mingzi Ran, Juan Guo, Chen Lu, Chengyu Fan, Jianjun Cheng, Weimin Zheng, Yue Hu, Tangsheng Lu, Gang Wang, Wenzhi Sun, Hailong Dong, Jingpeng Ge, Ji Hu
National Science Review September 5, 2025 Peer reviewed DOI: 10.1093/nsr/nwaf367 via OpenAlex
Summary
Ketamine rapidly elevates serotonin levels by inhibiting the serotonin transporter (SERT), which is vital for its antidepressant effects. This elevation activates vasoactive intestinal peptide (VIP)-expressing interneurons, essential for these rapid effects. Blocking VIP neurons inhibits the ketamine-like effects, indicating a specific mechanism at play. These findings suggest new pathways for developing fast-acting antidepressants.
Study at a glance
| Key finding | Ketamine's rapid antidepressant effects are mediated by its ability to elevate serotonin levels through SERT inhibition and activate VIP-expressing interneurons. |
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Abstract
-methyl-d-aspartate receptor (NMDAR) blockade is crucial for the rapid antidepressant effects of ketamine, the involvement of other mechanisms remains contentious, particularly regarding the role of serotonin, a key neurotransmitter in the target of traditional antidepressants. Here, we demonstrate that ketamine elevates serotonin levels by inhibiting the serotonin transporter (SERT). A cryogenic electron microscopy structure of ketamine-bound SERT in the outward-open conformation, resolved at 3.2 Å, indicates that ketamine binds to the central site of SERT. Elevated serotonin, along with NMDAR inhibition, induces ketamine-like rapid antidepressant effects. This increase in serotonin leads to the activation of vasoactive intestinal peptide (VIP)-expressing interneurons, which are essential for the rapid antidepressant effects of ketamine. Inhibition of VIP neurons blocks these effects and ketamine-like effects, highlighting a crucial cell type-specific mechanism. These findings identify a critical pathway in the rapid antidepressant actions of ketamine and offer potential pharmacological strategies for developing rapidly acting antidepressants.