Modulation of basal and stress-induced amygdaloid substance P release by the potent and selective NK1 receptor antagonist L-822429
Modulation of basal and stress-induced amygdaloid substance P release by the potent and selective NK1 receptor antagonist L-822429
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DOI：
10.1111/j.1471-4159.2008.05596.x
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发表时间：
2008-09-01
影响因子：
4.7
通讯作者：
Ebner, Karl
中科院分区：
文献类型：
--
作者：
Singewald, Nicolas;Chicchi, Gary G.;Ebner, Karl
研究表明，焦虑和压力反应受杏仁核内释放的P物质（SP）调节。然而，有一个重要的差距，在我们的知识有关的机制，调节细胞外SP在这个脑区。为了研究SP可能的自我调节作用，我们使用了选择性神经激肽-1（NK 1）受体拮抗剂，以调查是否NK 1受体的阻断导致改变的基础和/或应激诱发的SP释放内侧杏仁核（MeA），一个关键的大脑区域的功能参与SP传输增强焦虑反应应激暴露。体外结合和功能性受体测定表明，L-822429是一种有效的和选择性的大鼠NK 1受体拮抗剂。杏仁核内注射L-822429通过反向微透析增强基础，但衰减游泳应激诱导的SP释放，而L-822429的低亲和力对映体没有影响。使用光学和电子显微镜，突触之间的接触SP含纤维和树突表达NK 1受体被证明在内侧杏仁核。我们的研究结果表明，SP介导的神经传递的自我调节能力，在基础和应激诱导的SP释放的影响不同。在基础条件下，内源性SP可以作为一个信号，通过NK 1受体介导的负反馈作用，紧张性抑制其自身的释放，而在应激条件下，SP释放进一步促进NK 1受体的激活，可能导致高局部水平的SP和SP以较低亲和力结合的受体的活化。
It has been shown that anxiety and stress responses are modulated by substance P (SP) released within the amygdala. However, there is an important gap in our knowledge concerning the mechanisms regulating extracellular SP in this brain region. To study a possible self-regulating role of SP, we used a selective neurokinin-1 (NK1) receptor antagonist to investigate whether blockade of NK1 receptors results in altered basal and/or stress-evoked SP release in the medial amygdala (MeA), a critical brain area for a functional involvement of SP transmission in enhanced anxiety responses induced by stressor exposure. In vitro binding and functional receptor assays revealed that L-822429 represents a potent and selective rat NK1 receptor antagonist. Intraamygdaloid administration of L-822429 via inverse microdialysis enhanced basal, but attenuated swim stress-induced SP release, while the low-affinity enantiomer of L-822429 had no effect. Using light and electron microscopy, synaptic contacts between SP-containing fibres and dendrites expressing NK1 receptors was demonstrated in the medial amygdala. Our findings suggest self-regulatory capacity of SP-mediated neurotransmission that differs in the effect on basal and stress-induced release of SP. Under basal conditions endogenous SP can serve as a signal that tonically inhibits its own release via a NK1 receptor-mediated negative feedback action, while under stress conditions SP release is further facilitated by activation of NK1 receptors, likely leading to high local levels of SP and activation of receptors to which SP binds with lower affinity.