Corticotropin Releasing Factor-Norepinephrine Interactions in Stress & Depression

描述(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)的脑神经元在应激时被激活，这两种神经递质的激活与应激相关的行为反应有关，并且两者都可能与焦虑和抑郁有关。去甲肾上腺素和促肾上腺皮质激素释放因子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，这在应激反应中至关重要，而大脑中的其他CRF神经元也可能受到影响。脑内注射CRF可激活去甲肾上腺素神经元，尤其是蓝斑(LC)内有胞体的神经元。因此，有人提出，抑郁症可能是由于这些相互作用的敏感化而产生的，在这种机制中，每个系统都会激活另一个系统。除下丘脑室旁核和LC外，受累的大脑回路可能还包括杏仁中央核、终纹床核和外侧隔核。这项研究旨在将我们以前的工作重点放在CRF和NE的相互作用上，以阐明对慢性应激适应的细节，这可能为深入了解焦虑症和抑郁症的机制提供帮助。这项建议的具体目的是通过检测慢性应激动物的行为、去甲肾上腺素和HPA反应对急性应激和CRF的适应性，来确定这样的前馈假设是否合理。 这将通过评估行为反应、NE释放和血浆皮质酮对急性应激的反应来完成，并将这些与脑内注射CRF的反应进行比较。具体目的将是确定慢性应激大鼠对急性足部电击和局部注射CRF的神经化学(NE)和行为反应。将使用两种不同的慢性应激源范例：足部电击和暴露在捕食者(狐狸尿液)的气味中。NE反应最初将通过测量NE代谢物来确定，但随后将使用活体计时电流法和大鼠微透析进行研究。我们将确定和比较CRF受体的亚型(S)参与足底电击和CRF给药的反应。结果应该建立一个模型，并指出所涉及的大脑结构的性质，这样我们就可以随后检验前馈假说

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