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: 3395388
• 负责人: MARGARET C BOADLE-BIBER
• 金额: $ 18.32万
• 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/3395388
• 关键词: GABA receptor; adrenalectomy; alkaline phosphatase; amygdala; brain mapping; corticosteroid receptors; corticotropin releasing factor; dexamethasone; dorsal raphe nucleus; electrostimulus; environmental stressor; 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压力的影响， 随机提出响亮的声音，对生化指标的功能， 嘴侧投射的中脑5-羟色胺（5-HT，血清素） 含有大鼠大脑的神经元。它们的激活是由 色氨酸羟化酶的体外活性，该酶在 发射机（调制器）5-HT的合成，从而确定5-HT 空房的这种酶表现出两种不同的活性变化， 急性或反复声应力，1）快速可逆的增加， 在体外用碱性磷酸酶消除的活性，和2）更多的 酶活性持续增加，仅在重复声音后观察到 对碱性磷酸酶的作用不敏感的应激。两 活性的增加需要糖皮质激素的存在， 介导的杏仁中央核（ACE）。此外，本发明还提供了一种方法， 促肾上腺皮质激素释放因子（CRF）是已知的参与， 对急性声音应激的反应。我们的目标是进一步探索 通路，神经递质（调制器），介导的外观， 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，它们的尾部投射以及已知的 中脑中缝和I型和II型皮质酮的突触输入 大脑的受体。CRF的局部立体定位微量输注，其他 肽或经典的递质，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，鹅膏蕈氨酸 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学和 5-HT对声音应激反应的化学底物。使用HPLC-EC 为了定量在酶测定中形成的5-羟基色氨酸（5-HTP）， 5-HT及其代谢物5-羟基吲哚乙酸的组织水平，以及 在体内抑制脱羧后的组织5-HTP积累。的 可能介导酶活性两种变化的分子机制 也就是磷酸化或酶水平的增加 用这种酶的抗体这些研究可能与严重的 抑郁症，一种由压力引发的疾病， 5-HT、CRF和血浆糖皮质激素水平的改变也有牵连。