LEAD NEUROTOXICITY -- DOPAMINERGIC INVOLVEMENT

铅神经毒性——多巴胺能参与

• 批准号: 3250634
• 负责人: STEPHEN M LASLEY
• 金额: $ 7.67万
• 依托单位: TEXAS COLLEGE OF OSTEOPATHIC MEDICINE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-06-15 至 1987-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250634
• 关键词: apomorphine; atomic absorption spectrometry; butyrolactone; chromatography; dextroamphetamine; lead poisoning; neurons; neuropharmacologic agent; neuropharmacology; neurotoxins; neurotransmitter biosynthesis; scintillation counter; scintillation spectrometry; synapses; synaptosomes

The consequences of asymptomatic lead (Pb) exposure in man and the development of rational approaches for their prevention and treatment are matters of serious social concern. Research to characterize the behavioral impairments in children have described several suspected psychological effects. However, the magnitude and duration of exposure necessary to produce these deficits and the mechanisms underlying their manifestation have remained elusive. The issue remains a serious scientific concern because of the pervasive presence of Pb in many urban environments and the fact that animal studies have suggested the occurrence of behavioral alterations even when blood Pb values are low. Hypotheses regarding the effects of chronic developmental exposure on CNS neurotransmitter function in animals are poorly developed. The use of pharmacological agents to unmask subtle CNS dysfunctions has been fruitful in discriminating Pb toxicity in behavioral paradigms, but has not been advantageously applied to neurochemical measures. This research proposal is designed to extend previous findings of dopaminergic alterations in exposed rats to other dopaminergic drugs. Subsequently, the research will determine to what degree the Pb-induced changes are due to altered function of presynaptic receptors on dopaminergic nerve terminals and their relationship to associated changes in dopamine (DA) synthesis. These studies will utilize microdissection of rat brain structures in order to study discrete DA neuronal systems, liquid chromatography with electrochemical detection and scintillation counting to quantify drug-induced changes in DA content and synthesis rate, intravenous administration of radiolabeled amino acid precursor to measure synthesis, and a synaptosomal model to investigate specific synaptic processes. An animal model of asymptomatic Pb exposure will be utilized with hematologic and nutritional characteristics comparable to those in the pediatric population at risk. The proposed research will identify synaptic sites of impairment and indicate the importance of interactive influences produced by other impinging neurotransmitter systems by the selective use of specific neuropharmacological agents. As a result of information obtained on toxic mechanisms, more effective treatment of neurotoxicity can be devised as well as more appropriate methods for clinical evaluation of individuals at risk.

无症状铅（PB）暴露于人和的后果 开发预防和治疗的理性方法是 严重的社会关注问题。 研究以表征行为 儿童的障碍描述了一些可疑的心理 效果。 但是，需要的幅度和持续时间 产生这些赤字以及其表现形式的机制 仍然难以捉摸。 这个问题仍然是一个严重的科学问题 由于PB在许多城市环境中普遍存在 动物研究表明行为的发生的事实 即使血液PB值较低，也会改变。 关于 慢性发育暴露对CNS神经递质功能的影响 在动物中发育不良。 使用药理学剂 揭露CNS功能障碍在区分PB方面富有成果 行为范式的毒性，但尚未有利地应用 进行神经化学措施。 该研究建议旨在扩展 先前发现暴露大鼠多巴胺能改变到其他的发现 多巴胺能药物。 随后，研究将决定什么 程度PB诱导的变化是由于突触前的功能改变了 多巴胺能神经终末上的受体及其与 多巴胺（DA）合成的相关变化。 这些研究将利用 大鼠脑结构的显微减退以研究离散DA 神经元系统，具有电化学检测的液相色谱法和 闪烁计数以量化药物诱导的DA含量变化和 合成速率，静脉注射放射性标记的氨基酸 测量合成的前体和一个突触小体模型 特定的突触过程。 无症状PB暴露的动物模型 将使用血液学和营养特征使用 与处于危险中的小儿人群中的人相媲美。 提议 研究将确定损害的突触部位，并指出 互动影响的重要性 通过选择性使用特定的神经递质系统 神经药物剂。 由于有毒的信息 机理，更有效的神经毒性治疗可以设计为 以及更合适的方法用于对个体的临床评估 风险。