近日，南京医科大学周其冈等研究人员合作通过解除DRN中SERT与nNOS的关联来设计快速起效的抗抑郁药。2022年10月28日出版的《科学》杂志发表了这项成果。

严重抑郁症（MDD）是最常见的精神障碍之一。研究人员设计了一种快速起效的抗抑郁药，它通过破坏中缝背核（DRN）中5-羟色胺转运体（SERT）和神经元一氧化氮合成酶（nNOS）之间的相互作用而发挥作用。慢性不可预测的温和压力（CMS）选择性地增加了小鼠DRN中的SERT-nNOS复合物。在DRN中SERT-nNOS相互作用的增强引起了类似抑郁症的表型，并解释了CMS引起的抑郁行为。破坏SERT-nNOS的相互作用，通过增强前脑回路中的5-羟色胺信号产生快速的抗抑郁效果。

研究人员发现了一种小分子化合物ZZL-7，它在治疗2小时后产生了抗抑郁作用，而且没有不良的副作用。这种化合物或类似的试剂可以作为一种新的、快速作用的MDD疗法。

附：英文原文

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

Author: Nan Sun, Ya-Juan Qin, Chu Xu, Tian Xia, Zi-Wei Du, Li-Ping Zheng, An-an Li, Fan Meng, Yu Zhang, Jing Zhang, Xiao Liu, Ting-You Li, Dong-Ya Zhu, Qi-Gang Zhou

Issue&Volume: 2022-10-28

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.

DOI: abo3566

Source: https://www.science.org/doi/10.1126/science.abo3566