Inhibition of SERT and NMDAR synergistically confers rapid 2 antidepressant effects of ketamine by 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 instant download

Inhibition of SERT and NMDAR synergistically confers rapid 2 antidepressant effects of ketamine by 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 instant download

ABSTRACT 37 While N-methyl-D-aspartate receptor (NMDAR) blockade is crucial for the rapid 38 antidepressant effects of ketamine, the involvement of other mechanisms remains 39 contentious, particularly regarding the role of serotonin, a key neurotransmitter in the 40 target of traditional antidepressants. Here, we demonstrate that ketamine elevates serotonin levels by inhibiting the serotonin transporter (SERT). A cryogenic electron 41 microscopy structure of ketamine-bound SERT in the outward-open conformation, 42 resolved at 3.2 Å, indicates that ketamine binds to the central site of SERT. Elevated 43 serotonin, along with NMDAR inhibition, induces ketamine-like rapid antidepressant 44 effects. This increase in serotonin leads to the activation of vasoactive intestinal peptide 45 (VIP)-expressing interneurons, which are essential for the rapid antidepressant effects of 46 ketamine. Inhibition of VIP neurons blocks these effects and ketamine-like effects, 47 highlighting a crucial cell type-specific mechanism. These findings identify a critical 48 pathway in the rapid antidepressant actions of ketamine and offer potential 49 pharmacological strategies for developing rapidly acting antidepressants. 50 Keywords51 Ketamine; rapid antidepressant effects; SERT; NMDAR; vasoactive intestinal peptide–52 expressing interneurons 53 INTRODUCTION54 Major depressive disorder is characterized by a persistently low mood and the loss of 55 interest in activities, resulting in substantial impairment of daily life [1]. Conventional 56 antidepressants, such as selective serotonin (5-HT) reuptake inhibitors (SSRIs), often 57 take weeks to months to achieve their full effects [2-6]. Remarkably, a single 58 sub-anesthetic administration of the N-methyl-D-aspartate receptor (NMDAR) antagonist 59