SOUND STRESS, STEROIDS, CRF AND 5-HT NEURONAL FUNCTION

声音压力、类固醇、CRF 和 5-HT 神经元功能

• 批准号: 3395395
• 负责人: MARGARET C BOADLE-BIBER
• 金额: $ 18.05万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-12-01 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3395395
• 关键词: GABA receptor; adrenalectomy; alkaline phosphatase; amygdala; brain mapping; corticosteroid receptors; corticotropin releasing factor; dexamethasone; dorsal raphe nucleus; electrostimulus; environmental stressor; enzyme activity; enzyme induction /repression; experimental brain lesion; glucocorticoids; high performance liquid chromatography; hypophysectomy; inhibitor /antagonist; laboratory rat; locus coeruleus; loudness; mesencephalon; microinjections; neurochemistry; neuropeptide receptor; neuropharmacology; neurotoxins; noise biological effect; phosphorylation; serotonin receptor; stereotaxic techniques; tryptophan 5 monooxygenase

This project continues studies on the effects of an environmental stressor, randomly presented loud sound, on biochemical indices of the function of the rostrally projecting midbrain 5-hydroxytryptamine (5-HT, serotonin) containing neurons of rat brain. Their activation is monitored by the in vitro activity of tryptophan hydroxylase, the enzyme at is rate-limiting in the synthesis of the transmitter (modulator) 5-HT and thus determines 5-HT availability. This enzyme exhibits two distinct changes in activity to acute or repeated sound stress, 1) a rapidly reversible increase in activity that is abolished in vitro with alkaline phosphatase and 2) a more persistent increase in enzyme activity seen only after repeated sound stress that is insensitive to the action of alkaline phosphatase. Both increases in activity require the presence of glucocorticoid and are mediated over the amygdaloid central nucleus (ACE). In addition, corticotropin releasing factor (CRF) is known to be involved in the response to acute sound stress. The goal is to explore further the neural pathways, neurotransmitters (modulators) that mediate the appearance of the two types of increase in enzyme activity as well as the involvement of steroid hormones. Studies will focus on the ACE and associated lateral bed nucleus of the stria terminalis, their caudal projections as well as known synaptic inputs to the midbrain raphe and the type I and II corticosterone receptors of brain. Localized stereotaxic microinfusions of CRF, other peptides or classical transmitters, their antagonists, and of steroids and steroid antagonists, or discrete lesions (made by radiofrequency, ibotenic acid or the neurochemically selective neurotoxins, 6-hydroxydopamine or 5,7-dihydroxytryptamine) will be used to identify the neuroanatomical and chemical substrates of the 5-HT response to sound stress. HPLC-EC is used to quantitate 5-hydroxytryptophan (5-HTP) formed in the enzyme assay, tissue levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid, and tissue 5-HTP accumulation after inhibition of decarboxylation in vivo. The molecular mechanisms that may mediate the two changes in enzyme activity namely phosphorylation or an increase in enzyme level will also be explored with an antibody to the enzyme. These studies may have relevance for severe depression, a condition that can be triggered by stress and in which altered levels of 5-HT, CRF and plasma glucocorticoid have been implicated.

该项目继续研究环境应激源的影响， 随机呈现响亮的声音，对生化指标的作用 头端投射中脑的5-羟色胺(5-羟色胺，5-羟色胺) 含有大鼠大脑的神经元。它们的激活由In监控 色氨酸羟基酶的体外活性，该酶在 合成5-羟色胺的发送器(调制器)，从而确定5-羟色胺 可用性。这种酶表现出两种截然不同的活性变化 急性或反复的声音应激，1)迅速可逆的增加 在体外与碱性磷酸酶一起被取消的活性和2)更 只有在重复声音后才能看到酶活性的持续增加 对碱性磷酸酶的作用不敏感的压力。两者都有 活动的增加需要糖皮质激素的存在，并且 通过杏仁中央核(ACE)进行调节。此外, 促肾上腺皮质激素释放因子(CRF)被认为参与了 对急性声音应激的反应。我们的目标是进一步探索神经 途径，神经递质(调节物)，中介的外观 两种类型的酶活性增加以及参与 类固醇激素。研究将集中在ACE和相关的侧床 终纹的核、其尾侧投射以及已知 中脑中缝和I型和II型皮质酮的突触输入 大脑的受体。CRF等的局部立体定向微量注射 多肽或经典递质，它们的拮抗剂，以及类固醇和 类固醇拮抗剂，或离散病变(由射频、鹅膏制成) 酸或神经化学选择性神经毒素，6-羟基多巴胺或 5，7-二羟色胺)将用于识别神经解剖和 5-羟色胺的化学底物对声音应激的反应。采用高效液相色谱-电化学法 为了定量酶分析中形成的5-羟色氨酸(5-HTP)， 组织中5-羟色胺及其代谢物5-羟基吲哚乙酸和 组织中5-HTP在体内被抑制脱羧基后蓄积。这个 可能调节这两种酶活性变化的分子机制 也就是说，磷酸化或酶水平的增加也将被探索。 带有这种酶的抗体。这些研究可能与严重的 抑郁，一种可以由压力引发的状况，在这种情况下 5-羟色胺、CRF和血浆糖皮质激素水平的改变也与此有关。