REGULATION OF PERIPHERAL AUTONOMIC FUNCTION AND NEUROENDOCRINE RESPONSES

末梢自主功能和神经内分泌反应的调节

• 批准号: 2579634
• 负责人: I J KOPIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2579634
• 关键词: autonomic nervous system; neuroendocrine system; peripheral nervous system

The main objectives of this project are to determine the roles of catecholamines in brain functions that regulate motor activity, neuroendocrine secretion, and autonomic function. In vivo microdialysis is used to monitor levels of monoamines and their metabolites in extracellular fluid in specific brain regions, with simultaneous measurements of arterial plasma levels of norepinephrine (NE), epinephrine (EPI), and ACTH. Microdialysis probes with an attached infusion microcannulae are used to introduce drugs or isotopically-labelled compounds and sample extracellular fluid in the same region. Brain lesions are made surgically or by use of toxins specific to particular cell types. HPLC and liquid scintillation spectrophotometry are used in assays of materials in the microdialysates and in situ hybridization used to examine brain regional levels of mRNA encoding CRH. In rats with unilateral striatonigral dopamine (DA) neurons destroyed with 6-OHDA, DA formation from locally perfused DOPA was detected but was less on the lesioned than on the intact side. Clorgyline (an inhibitor of MAO-A), augmented DA production from DOPA both on the lesioned and the intact side, whereas deprenyl (an inhibitor of MAO-B) had no effect. Neuroendocrine responses to a variety of stressors (handling, immobilization, subcutaneous formalin injection, insulin, hemorrhage, or cold) indicated stressor-specific patterns. For example, insulin-induced hypoglycemia evoked marked, correlated increases in EPI and ACTH levels, whereas cold exposure increased plasma NE levels disproportionately compared with ACTH responses, and hypotensive hemorrhage increased ACTH levels disproportionately compared with catecholamine responses. Administration of cortisol inhibited basal and immobilization stress-induced NE release and catecholamine synthesis in the paraventricular nucleus (PVN). After adrenalectomy, release was enhanced, and the effects of adrenalectomy were reversed by treatment with replacement doses of cortisol. Thus, central noradrenergic pathways ascending from medullary centers participate in feedback inhibition of HPA axis activity exerted by circulating glucocorticoids. After brainstem hemisection, which interrupts noradrenergic pathways from the A1 and A2 areas to the PVN, immobilization stress-induced NE release in the ipsilateral PVN was reduced much more than in the contralateral PVN, whereas NE release in the central nucleus of the amygdala was unaffected on either side. Both basal levels and stress-induced enhancement of PVN mRNA encoding CRH were diminished ipsilateral to the hemisection. Plasma ACTH responses to immobilization, however, were uninfluenced by brainstem hemisection. This indicates that there is sufficient CRH release from only one PVN to elicit an unimpaired ACTH response to immobilization.

该项目的主要目标是确定以下方面的作用： 脑功能中的儿茶酚胺调节运动活动， 神经内分泌和自主神经功能。体内微透析 用于监测单胺及其代谢物的水平， 特定脑区的细胞外液，同时 去甲肾上腺素（NE）的动脉血浆水平的测量， 肾上腺素（EPI）和ACTH。微透析探针， 输注微插管用于引入药物或 同位素标记的化合物和样品细胞外液中 同一地区。脑部损伤是通过手术或使用毒素造成的 对特定细胞类型有特异性。HPLC和液体闪烁 分光光度法用于测定微透析液中的物质 原位杂交用于检测大脑区域mRNA水平 编码CRH。在单侧纹状体黑质多巴胺（DA）神经元 用6-OHDA破坏，从局部灌注的多巴形成的DA被破坏。 检测到，但在病变侧比在完整侧少。氯吉林 (an MAO-A的抑制剂），增加多巴胺的生产从多巴上都对 损伤侧和完整侧，而丙炔苯丙胺（MAO-B的抑制剂） 没有效果。神经内分泌对各种应激源的反应 （处理、固定、皮下福尔马林注射、胰岛素， 出血或寒冷）指示应激源特异性模式。例如，在一个示例中， 胰岛素诱导的低血糖引起EPI显著相关增加 和ACTH水平，而冷暴露增加血浆NE水平， 与ACTH反应相比不成比例， 出血增加ACTH水平不成比例相比， 儿茶酚胺反应。给予皮质醇可抑制基础和 束缚应激诱导NE释放和儿茶酚胺合成 室旁核（PVN）。肾上腺切除术后， 增强，肾上腺切除术的影响被逆转的治疗 用皮质醇替代因此，中枢去甲肾上腺素能通路 从延髓中枢上行参与反馈抑制 HPA轴活性由循环糖皮质激素产生。脑干后 半切，中断A1和A2的去甲肾上腺素能通路 在PVN的区域，固定应激诱导的NE释放 同侧PVN的缩小程度远大于对侧PVN， 而杏仁核中央核的NE释放不受影响 两边都是PVN的基础水平和应激诱导的增强 编码CRH的mRNA在半切同侧减少。血浆 ACTH反应制动，然而，不受脑干 半切术这表明有足够的CRH释放， 仅一个PVN以引起对制动的未受损的ACTH反应。