Different roles of distinct serotonergic pathways in anxiety-like behavior, antidepressant-like, and anti-impulsive effects
Different roles of distinct serotonergic pathways in anxiety-like behavior, antidepressant-like, and anti-impulsive effects
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DOI：
10.1016/j.neuropharm.2019.107703
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发表时间：
2020-05-01
影响因子：
4.7
通讯作者：
Yoshioka, Mitsuhiro
中科院分区：
文献类型：
--
作者：
Ohmura, Yu;Tsutsui-Kimura, Iku;Yoshioka, Mitsuhiro
5-羟色胺能药物已被广泛用于精神疾病的治疗，但这些药物的治疗效果不够，并且这些药物常常引起严重的副作用。为了克服这些问题，我们需要明确每种心理功能背后的不同的多巴胺能通路。临床前研究表明，中枢多巴胺能系统参与了几种情绪/认知功能，包括焦虑、抑郁和冲动控制，但目前尚不清楚每种功能是否由不同的多巴胺能系统调节。我们使用光遗传学策略来增加小鼠的中枢多巴胺能活性并评估行为后果。药理学和遗传学工具被用来确定负责观察到的效果的5-HT受体的亚型。我们证明，中缝正中核的多巴胺能激活增强焦虑样行为，中缝背核的多巴胺能激活产生抗抑郁样作用，中缝正中核或中缝背核的多巴胺能激活抑制冲动行为。我们还发现，不同的多巴胺能末梢，腹侧海马，腹侧被盖区/黑质，和丘脑底/丘脑旁核，分别参与调节焦虑样行为，抗抑郁样，抗冲动效应。此外，我们发现，使用三重转基因小鼠，5-HT 2C受体的刺激是引起焦虑样行为所必需的，但不是发挥抗冲动作用。这些结果表明需要特定途径的治疗，并提供重要的见解，这将有助于更有效和更安全的治疗方法的发展。这篇文章是题为“血清素研究：跨越尺度和边界”的特刊的一部分。
Serotonergic agents have been widely used for treatment of psychiatric disorders, but the therapeutic effects are insufficient and these drugs often induce severe side effects. We need to specify the distinct serotonergic pathways underlying each mental function to overcome these problems. Preclinical studies have demonstrated that the central serotonergic system is involved in several emotional/cognitive functions including anxiety, depression, and impulse control, but it remains unclear whether each function is regulated by a different serotonergic system. We used optogenetic strategy to increase central serotonergic activity in mice and evaluated the behavioral consequences. Pharmacological and genetic tools were used to determine the subtype of 5-HT receptors responsible for the observed effects. We demonstrated that the serotonergic activation in the median raphe nucleus enhanced anxiety-like behavior, the serotonergic activation in the dorsal raphe nucleus exerted antidepressant-like effects, and the serotonergic activation in the median or dorsal raphe nucleus suppressed impulsive action. We also found that different serotonergic terminals, ventral hippocampus, ventral tegmental area/substantia nigra, and subthalamic/parasubthalamic nucleus, are involved in regulating anxiety-like behavior, antidepressant-like, and anti-impulsive effects, respectively. Furthermore, we found, using triple-transgenic mice, that the stimulation of the 5-HT2C receptor is required to evoke anxiety-like behavior, but not to exert anti-impulsive effects. These results suggest the need for pathway-specific treatments and provide important insights that will help the development of more effective and safer therapeutics.This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.