Stress-induced release of substance P in the locus coeruleus modulates cortical noradrenaline release
Stress-induced release of substance P in the locus coeruleus modulates cortical noradrenaline release
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DOI：
10.1007/s00210-007-0185-3
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发表时间：
2007-10-01
影响因子：
3.6
通讯作者：
Singewald, Nicolas
中科院分区：
文献类型：
--
作者：
Ebner, Karl;Singewald, Nicolas
多项证据表明神经肽物质 P (SP) 参与情绪行为的调节。 SP 和去甲肾上腺素能系统之间的相互作用被认为对于调节压力、抑郁和焦虑机制很重要；然而，到目前为止，大多数证据都是基于对未受到攻击和/或麻醉的动物的研究。因此，通过在自由活动的动物中使用双探针微透析方法，本研究的目的是调查相关压力源是否可以触发蓝斑（LC）中SP的释放，以及这种反应是否以及如何调节LC和内侧前额叶皮层（mPFC）中去甲肾上腺素（NA）的传输，内侧前额叶皮层是参与情绪处理的重要LC末端区域。虽然证实了之前的报道，即神经激肽 1 受体 (NK1R) 拮抗剂在静息条件下激活皮质去甲肾上腺素能传递，但我们提供的证据表明，这种相互作用在压力挑战期间是相反的。我们的结果表明，强迫游泳显着增强了 LC 中 SP 和 NA 的释放。向 LC 中施用选择性 NK1R 拮抗剂可增强 LC 内的 NA 反应，但消除了应激诱导的 mPFC 内 NA 释放的增加。这些发现表明，应激诱导的 LC 内内源性细胞外 SP 水平增加，对通向 mPFC 的去甲肾上腺素能通路产生促进作用。 NK1R 拮抗剂可能通过增强 NA 和 LC 中的自身抑制来减弱应激诱导的该通路过度激活，可能有助于这些已知可改善应激相关疾病症状的药物的治疗效果。
Several lines of evidence implicate the neuropeptide substance P (SP) in the modulation of emotional behavior. Interaction between SP and noradrenergic systems has been proposed to be important in the regulation of stress, depression, and anxiety mechanisms; however, most evidence so far is based on studies in unchallenged and/or anesthetized animals. Thus, by using a dual-probe microdialysis approach in freely moving animals, the aim of the present study was to investigate whether a relevant stressor can trigger the release of SP in the locus coeruleus (LC) and whether and how this response modulates noradrenaline (NA) transmission both in the LC and in the medial prefrontal cortex (mPFC), an important LC terminal region involved in emotional processing. While confirming previous reports that neurokinin 1 receptor (NK1R) antagonists activate cortical noradrenergic transmission under resting conditions, we present evidence that this interaction is opposite during stress challenge. Our results show that exposure to forced swimming considerably enhanced the release of SP and NA in the LC. Administration of a selective NK1R antagonist into the LC potentiated this NA response within the LC but abolished the stress-induced increase in NA release within the mPFC. These findings demonstrate stress-induced increase in endogenous extracellular SP levels within the LC exerting a facilitatory effect on the noradrenergic pathway to the mPFC. The attenuation of stress-induced hyperactivation of this pathway by NK1R antagonists, presumably via enhancing NA and autoinhibition in the LC, may contribute to the therapeutic efficacy of these drugs known to ameliorate symptoms of stress-related disorders.