Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation
Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation
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DOI：
10.1523/jneurosci.2584-06.2007
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发表时间：
2007-06-27
影响因子：
5.3
通讯作者：
Tecott, Laurence H.
中科院分区：
文献类型：
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作者：
Heisler, Lora K.;Pronchuk, Nina;Tecott, Laurence H.
过去 30 年来，血清素 [5-羟色胺 (5-HT)] 神经传递与下丘脑-垂体-肾上腺 (HPA) 轴之间的动态相互作用已得到广泛研究，但这种相互作用的潜在机制尚未明确。一种很少受到关注的可能性是，5-HT 通过激活下丘脑 (PVH) 室旁核 (PVH) 中的血清素 2C 受体 (5-HT(2C)Rs) 来调节上游促肾上腺皮质激素释放激素 (CRH) 信号系统。通过对野生型啮齿动物和 5-HT2CR 缺陷小鼠的补充方法，我们确定 5-HT(2C)R 对于 5-HT 诱导的 HPA 轴激活是必需的。我们使用激光捕获 PVH 显微切割，然后进行微阵列分析来比较 13 个 5-HTR 的表达。仅 5-HT2CR 和 5-HT1DR 转录物被一致鉴定为存在于 PVH 中，其中 5-HT2CR 的表达水平明显较高。原位杂交组织化学证实了PVH中5-HT(2C)Rs的丰富表达。双神经组织化学标记显示，大约一半的含有 CRH 的 PVH 神经元共表达 5-HT2CR mRNA。我们观察到，PVH CRH 神经元在高亲和力 5-HT2CR 激动剂存在下持续去极化，这种效应被 5-HT2CR 拮抗剂阻断。 5-HT(2C)Rs 的基因失活导致 CRH mRNA 下调，并在给予 5-HT 化合物后减弱 CRH 和皮质酮的释放，这支持了 5-HT(2C)Rs 在 CRH 神经元活动中的重要性。因此，这些发现为长期观察到的 HPA 轴刺激响应 5-HT 提供了机制解释，从而深入了解介导复杂的神经内分泌应激反应的神经回路。
The dynamic interplay between serotonin [5-hydroxytryptamine (5-HT)] neurotransmission and the hypothalamic-pituitary-adrenal (HPA) axis has been extensively studied over the past 30 years, but the underlying mechanism of this interaction has not been defined. A possibility receiving little attention is that 5-HT regulates upstream corticotropin-releasing hormone (CRH) signaling systems via activation of serotonin 2C receptors (5-HT(2C)Rs) in the paraventricular nucleus of the hypothalamus (PVH). Through complementary approaches in wild- type rodents and 5-HT2CR-deficient mice, we determined that 5-HT(2C)Rs are necessary for 5-HT-induced HPA axis activation. We used laser-capture PVH microdissection followed by microarray analysis to compare the expression of 13 5-HTRs. Only 5-HT2CR and 5-HT1DR transcripts were consistently identified as present in the PVH, and of these, the 5-HT2CR was expressed at a substantially higher level. The abundant expression of 5-HT(2C)Rs in the PVH was confirmed with in situ hybridization histochemistry. Dual-neurohistochemical labeling revealed that approximately one-half of PVH CRH-containing neurons coexpressed 5-HT2CR mRNA. We observed that PVH CRH neurons consistently depolarized in the presence of a high- affinity 5-HT2CR agonist, an effect blocked by a 5-HT2CR antagonist. Supporting the importance of 5-HT(2C)Rs in CRH neuronal activity, genetic inactivation of 5-HT(2C)Rs produced a downregulation of CRH mRNA and blunted CRH and corticosterone release after 5-HT compound administration. These findings thus provide a mechanistic explanation for the longstanding observation of HPA axis stimulation in response to 5-HT and thereby give insight into the neural circuitry mediating the complex neuroendocrine responses to stress.