Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT_2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT_2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT_2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT_2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT_2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT_2B-receptor stimulation by BW723C86 counteracted 5-HT_1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT_2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b ^5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT_2B receptor expression in serotonergic neurons. In Htr2b ^5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b ^lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT_1A-autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT_2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT_2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT_1A-negative autoreceptor.

中文翻译：

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血清素2B受体对蕾菲血清素神经元的正向调节作用。

血清素是一种涉及许多精神疾病的神经递质。在人类中，缺乏5-HT _2B受体与血清素依赖性表型有关，包括冲动性和自杀性。小鼠中缺乏5-HT _2B受体消除了直接靶向血清素能神经元的分子的作用，包括苯丙胺衍生物5-羟色胺释放剂和选择性5-羟色胺再摄取抑制剂抗抑郁药。在这项工作中，我们测试了5-HT _2B受体直接和正向调节缝线5-羟色胺神经元活性的假说。通过离体电生理记录，我们报告了5-HT _2B的刺激受体激动剂BW723C86增加了血清素Pet1阳性神经元的放电频率。这些神经元中5-HT _2B受体的病毒过表达增加了它们的兴奋性。此外，BW723C86在体内对5-HT _2B受体的刺激抵消了野生型小鼠5-HT _1A受体依赖的放电率和低温反应的降低。通过有条件的遗传消融，专门和专有地消除Pet1阳性血清素神经元中的5-HT _2B受体表达（Htr2b ^5-HTKO小鼠），我们证明了MDMA（3,4-亚甲二氧基-甲基苯丙胺）的行为和致敏作用，以及抗抑郁药氟西汀的急性行为和慢性神经源性作用，需要5-羟色胺_2B受体在5-羟色胺能神经元中的表达。通过体内细胞外记录评估，在Htr2b ^5-HTKO小鼠中，背缝血清素神经元显示出比对照组Htr2b ^{lox / lox}小鼠更低的放电频率，并且观察到更强的5-HT _1A -autoreceptor刺激的低温效应。对DOI（2,5-二甲氧基-4-碘安非他明）的头部抽搐反应的增加进一步证实了由于缺乏5-HT _2B而导致的血清素能降低血清素神经元中的受体。总之，这些观察结果表明5-HT _2B受体以与已知的5-HT _1A阴性自身受体相反的方式充当5-羟色胺Pet1阳性神经元的直接正调节剂。