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Papers of the Week


2022 Oct 28


Science


378


6618

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN.

Authors

Sun N, Qin Y-J, Xu C, Xia T, Du Z-W, Zheng L-P, Li A-A, Meng F, Zhang Y, Zhang J, Liu X, Li T-Y, Zhu D-Y, Zhou Q-G
Science. 2022 Oct 28; 378(6618):390-398.
PMID: 36302033.

Abstract

Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.