Overexpression of 5-HT1B receptor in dorsal raphe nucleus using herpes simplex virus gene transfer increases anxiety behavior after inescapable stress
Overexpression of 5-HT1B receptor in dorsal raphe nucleus using herpes simplex virus gene transfer increases anxiety behavior after inescapable stress
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DOI：
10.1523/jneurosci.22-11-04550.2002
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发表时间：
2002-06-01
影响因子：
5.3
通讯作者：
Neumaier, JF
中科院分区：
文献类型：
--
作者：
Clark, MS;Sexton, TJ;Neumaier, JF
5-HT1B自身受体与动物应激模型有关，并通过氟西汀等抗抑郁药选择性再摄取抑制剂进行调节。这些终末自身受体调节大鼠前脑中缝背核（DRN）投射的5-羟色胺释放。然而，以前不可能选择性地操纵5-HT1B自身受体活性而不改变介导不同行为反应的其他神经元中的5-HT1B活性。因此，我们已经开发了一种病毒介导的基因转移策略来表达血凝素标记的5-HT1B，并在DRN中操纵这些自身受体。绿色荧光蛋白（GFP）从同一扩增子上的单独转录单位共表达，以帮助监测感染和表达。我们证实了这两个转基因蛋白的表达和生物活性在体外。将HA-5-HT 1B受体直接注射入DRN后，HA-5-HT 1B受体在多巴胺能神经元中表达，并转位至前脑。将HA-5-HT1B的DRN表达对应激诱导行为的影响与仅接受GFP扩增子的对照大鼠进行比较。在强迫游泳试验中，不动性没有变化。然而，HA-5-HT1B的表达显着减少入口到一个开放的领域竞技场的中心区域后，水约束应力不改变整体运动活动，但不是在没有应力暴露。HA-5-HT1B表达也减少了水限制后进入高架十字迷宫开放臂的次数。由于这些测试是敏感的焦虑样行为的增加，我们的研究结果表明，过度活跃的5-HT1B自身受体在DRN神经元可能是一个重要的介质的病理反应，压力事件。
5-HT1B autoreceptors have been implicated in animal models of stress and are regulated selectively by serotonin-selective reuptake inhibitors such as fluoxetine. These terminal autoreceptors regulate serotonin release from dorsal raphe nucleus (DRN) projections throughout rat forebrain. However, it has not been previously possible to manipulate 5-HT1B autoreceptor activity selectively without also changing 5-HT1B activity in other neurons mediating different behavioral responses. Therefore, we have developed a viral-mediated gene transfer strategy to express hemagglutinin-tagged 5-HT1B and manipulate these autoreceptors in DRN. Green fluorescent protein (GFP) was coexpressed from a separate transcriptional unit on the same amplicon to assist in monitoring infection and expression. We confirmed the expression and biological activity of both transgenic proteins in vitro. When injected directly into DRN using stereotaxic procedure, HA-5-HT1B receptors were expressed in serotonergic neurons and translocated to the fore-brain. The effect of DRN expression of HA-5-HT1B on stress-induced behaviors was compared with control rats that received GFP-only amplicons. There was no change in immobility in the forced swim test. However, HA-5-HT1B expression significantly reduced entrances into the central region of an open-field arena after water-restraint stress without altering overall locomotor activity, but not in the absence of stress exposure. HA-5-HT1B expression also reduced entries into the open arms of the elevated plus maze after water restraint. Because these tests are sensitive to increases in anxiety-like behavior, our results suggest that overactivity of 5-HT1B autoreceptors in DRN neurons may be an important mediator of pathological responses to stressful events.