CRF-Norepinephrine Interactions in Stress and Depression

CRF-去甲肾上腺素在压力和抑郁中的相互作用

基本信息

批准号：
7013249
负责人：
Adrian John Dunn
金额：
$ 28.04万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-01 至 2009-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): There is extensive evidence that brain neurons containing norepinephrine (NE) and corticotropin-releasing factor (CRF) are activated during stress, that activations of these two neurotransmitters are related to stress-related behavioral responses, and that both may be involved in anxiety and depression. Interactions between neurons containing NE and CRF are extensive. Noradrenergic neurons are among those that can stimulate CRF-containing neurons initiating the activation of the hypothalamo-pituitary-adrenal (HPA) axis, critical in the stress response, while other CRF-neurons in the brain may also be affected. Intracerebral administration of CRF activates NE neurons, especially those with cell bodies in the locus coeruleus (LC). Thus it has been proposed that depression may result from a sensitization of these interactions, creating a "feed forward" mechanism in which each system activates the other. The brain circuits involved may include the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the lateral septum, in addition to the hypothalamic paraventricular nucleus and the LC. The research proposed aims to focus our previous work on CRF and NE interactions to elucidate details of the adaptations to chronic stress that may provide insight into the mechanisms involved in anxiety disorders and depression. The specific aim of this proposal is to determine whether or not such a feed-forward hypothesis is reasonable, by examining the adaptation in the behavioral, noradrenergic and HPA responses to acute stress and CRF in chronically stressed animals. This will be done by assessing the behavioral responses and NE release and plasma corticosterone in response to acute stress, and comparing these to the responses to intracerebral injection of CRF. The specific aims will be to determine the neurochemical (NE) and behavioral responses of chronically stressed rats to acute footshock and to CRF injected locally into the LC. Two different chronic stressor paradigms will be used: footshock and exposure to the odor of a predator (fox urine). The NE responses will be determined initially by measuring NE metabolites, but this will be followed by studies using in vivo chronoamperometry and microdialysis in rats. We will determine and compare the subtype(s) of CRF receptor involved in the responses to footshock and to CRF administration. The results should establish a model and indicate the nature of the cerebral structures involved, so that we can subsequently test the feed-forward hypothesis

描述（由申请人提供）：有大量证据表明，含有去甲肾上腺素（NE）和促肾上腺皮质激素释放因子（CRF）的大脑神经元在压力期间被激活，这两种神经递质的激活与压力相关的行为反应有关，并且两者都可能涉及焦虑和抑郁。含有 NE 和 CRF 的神经元之间的相互作用是广泛的。去甲肾上腺素能神经元可以刺激含有 CRF 的神经元，启动下丘脑-垂体-肾上腺 (HPA) 轴的激活，这对应激反应至关重要，而大脑中的其他 CRF 神经元也可能受到影响。脑内给予 CRF 可激活 NE 神经元，尤其是蓝斑 (LC) 中具有细胞体的神经元。因此，有人提出，抑郁症可能是由于这些相互作用的敏感化造成的，从而产生了一种“前馈”机制，其中每个系统都激活另一个系统。所涉及的脑回路除了下丘脑室旁核和LC外，还可能包括杏仁核中央核、终纹床核和侧隔。拟议的研究旨在将我们之前的工作重点放在 CRF 和 NE 相互作用上，以阐明对慢性压力的适应细节，这可能有助于深入了解焦虑症和抑郁症的机制。该提案的具体目的是通过检查长期应激动物对急性应激和 CRF 的行为、去甲肾上腺素能和 HPA 反应的适应性，确定这种前馈假设是否合理。这将通过评估对急性应激的行为反应、NE 释放和血浆皮质酮，并将这些反应与脑内注射 CRF 的反应进行比较来完成。具体目标是确定长期应激大鼠对急性足部电击和局部注射到 LC 中的 CRF 的神经化学 (NE) 和行为反应。将使用两种不同的慢性应激范例：足部电击和暴露于捕食者的气味（狐狸尿液）。 NE 反应最初将通过测量 NE 代谢物来确定，但随后将使用大鼠体内计时电流分析法和微透析进行研究。我们将确定并比较参与足部电击反应和 CRF 给药反应的 CRF 受体亚型。结果应该建立一个模型并表明所涉及的大脑结构的性质，以便我们随后检验前馈假设