Serotonin (5HT), fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior
Serotonin (5HT), fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior
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DOI：
10.1534/genetics.104.032540
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发表时间：
2005-03-01
期刊：
影响因子：
3.3
通讯作者：
Sze, JY
中科院分区：
文献类型：
--
作者：
Dempsey, CM;Mackenzie, SM;Sze, JY
针对阴囊能系统的药物是最常用的治疗药物，用于治疗广泛的行为和神经疾病。然而，药物的作用机制仍然是一个猜测。在这里，我们剖析了5-羟色胺(5-羟色胺)、选择性5-羟色胺再摄取抑制剂(SSRI)、氟西汀(百忧解)、三环类抗抑郁药丙咪嗪和多巴胺的遗传靶点。以线虫产卵行为中已证实的阴囊激素能反应为范式，我们发现氟西汀和丙咪嗪在5羟色胺再摄取转运体(SERT)和5羟色胺受体上的作用是可分离的机制。即使完全缺乏5-羟色胺或SERT的突变株也能对氟西汀和丙咪嗪产生部分反应。此外，可以认识到每种药物的不同机制可以调节这些反应。5-HT1受体SER-1的缺失可取消对5-羟色胺的反应，但对丙咪嗪的反应影响不大，对氟西林的反应无影响。相反，缺失5HT2受体SER-4会对丙咪嗪产生显著的耐药性，而对5HT或氟西汀的反应保持不变。此外，氟西汀可以通过GQ蛋白EGL-30刺激产卵，而不依赖于SER-1、SER-4或5HT。我们还发现，多巴胺通过5羟色胺门控离子通道MOD-1信号通路拮抗5羟色胺的作用，提示该通道活动与5羟色胺和多巴胺信号相偶联。这些结果表明，这些药物在特定受体亚型上的作用可能决定它们的治疗效果。SSRI和三环抗抑郁药可能独立于5-羟色胺的突触水平调节5-羟色胺的输出。
Drugs that target the scrotonergic system are the most commonly prescribed therapeutic agents and are used for treatment of a wide range of behavioral and neurological disorders. However, the mechanism of the drug action remain a conjecture. Here, we dissect the genetic targets of serotonin (5HT), the selective 5HT reuptake inhibitor (SSRI) fluoxetine (Prozac), the tricyclic antidepressant imipramine, and dopamine. Using the well-established scrotonergic response in C. elegans egg-laying behavior as a paradigm, we show that action of fluoxetine and imipramine at the 5HT reuptake transporter (SERT) and at 5HT receptors are separable mechanisms. Even mutants completely lacking 5HT or SERT can partially respond to fluoxetine and imipramine. Furthermore, distinct mechanisms for each drug can be recognized to mediate these responses. Deletion of SER-1, a 5HT1 receptor, abolishes the response to 5HT but has only a minor effect on the response to imipramine and no effect on the response to fluoxerinc. In contrast, deletion of SER-4, a 5HT2 receptor, confers significant resistance to imipramine while leaving the responses to 5HT or fluoxetine intact. Further, fluoxetine can stimulate egg laying via the Gq protein EGL-30, independent of SER-1, SER-4, or 5HT. We also show that dopamine antagonizes the 5HT action via the 5HT-gated ion channel MOD-1 signaling, Suggesting that this channel activity couples 5HT and dopamine signaling. These results suggest that the actions of these drugs at specific receptor Subtypes could determine their therapeutic efficacy. SSRIs and tricyclic antidepressarus may regulate 5HT outputs independently of synaptic levels of 5HT.