Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN
Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN
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通过在 DRN 中将 SERT 与 nNOS 分离来设计快速起效的抗抑郁药
DOI：
10.1126/science.abo3566
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发表时间：
2022-10-28
期刊：
影响因子：
56.9
通讯作者：
Zhou, Qi-Gang
中科院分区：
文献类型：
--
作者：
Sun, Nan;Qin, Ya-Juan;Zhou, Qi-Gang
重性抑郁障碍（Major Depression Disorder，MDD）是最常见的精神障碍之一。我们设计了一种快速起效的抗抑郁药，通过破坏中缝背核（DRN）中5-羟色胺转运体（SERT）和神经元型一氧化氮合酶（nNOS）之间的相互作用来发挥作用。慢性不可预测的轻度应激（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抑郁样表型，并解释CMS诱导的抑郁行为。破坏SERT-nNOS相互作用通过增强前脑回路中的5-羟色胺信号传导产生快速起效的抗抑郁作用。我们发现了一种小分子化合物ZZL-7，在治疗后2小时引起抗抑郁作用，没有不良副作用。这种化合物或类似试剂可能作为一种新的、快速作用的MDD治疗方法。描述一类新型抗抑郁药物目前可用的抗抑郁药物具有令人不快的副作用、成瘾性，或可诱发精神分裂症。因此，开发没有这些缺点的快速起效的抗抑郁药是一个重要的神经药理学目标。Sun等人发现，将5-羟色胺转运体从一氧化氮合酶中分离出来，可以特异性地降低中缝背核（dorsal raphe nucleus）脑区细胞间5-羟色胺浓度。破坏这种相互作用增强了该区域的多巴胺能神经元活动，并显著促进5-羟色胺释放到内侧前额叶皮层，从而产生快速起效的抗抑郁作用。一氧化氮合酶-5-羟色胺转运体相互作用的小分子阻滞剂在动物模型中具有快速起效的抗抑郁作用。-PRS一种小分子化合物可能有助于通过调节多巴胺能神经元的放电来开发快速起效的抗抑郁药。
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. Description A new class of antidepressant drugs Presently available antidepressant drugs have unpleasant side effects, addictive properties, or can induce schizophrenia. Developing fast-onset antidepressants without these drawbacks is thus an important neuropharmacological goal. Sun et al. discovered that dissociating the serotonin transporter from nitric oxide synthase specifically reduced intercellular serotonin concentration in a brain region called the dorsal raphe nucleus. Disrupting this interaction enhanced serotonergic neuron activity in this area and dramatically promoted serotonin release into the medial prefrontal cortex, thereby producing a fast-onset antidepressant effect. A small-molecule blocker of the nitric oxide synthase–serotonin transporter interaction had a fast-onset antidepressant effect in an animal model. —PRS A small-molecule compound may help in the development of rapidly acting antidepressants by regulating the firing of serotonergic neurons.