NMDA RECEPTOR AND BEHAVIORAL TOXICITY OF LEAD

NMDA 受体和铅的行为毒性

• 批准号: 2154749
• 负责人: Deborah A Cory-Slechta
• 金额: $ 26.55万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2154749
• 关键词: NMDA receptors; animal developmental psychology; autoradiography; behavior disorders; behavior test; cerebellum; cingulate gyrus; corpus striatum; cytotoxicity; early experience; environmental toxicology; frontal lobe /cortex; hippocampus; image processing; laboratory rat; lead poisoning; learning disorders; memory disorders; neurotoxins; parietal lobe /cortex; pharmacokinetics; receptor binding; statistics /biometry; tissue /cell preparation

Recently published cellular and biochemical studies suggest that Pb exposure may impair learning and memory functions through an inhibitory action on the NMDA receptor complex. this notion of an NMDA-based mechanism for the behavioral toxicity of Pb has appeal because: a) it could account for behavioral toxicity in response to Pb exposures either early in development or under conditions of occupational exposure; b) it could explain the preferential vulnerability to Pb of learning relative to performance functions; c) it is consistent with reports of preferential accumulation of Pb in hippocampus, an area of NMDA receptor density; d) it would provide a mechanism for cognitive deficits in the absence of a defined morphological lesion. For such a contention to have credence or clinical significance, however, requires that NMDA-based sensitivity be altered at a behavioral level and/or that compounds acting at the NMDA receptor complex could alter Pb-induced changes in learning. New data from this laboratory supporting that contention include an attenuation and potentiation, respectively, of the accuracy-impairing effects of the non-competitive NMDA antagonist MK-801 and the glutamate agonist NMDA in Pb-exposed rats relative to controls on a multiple schedule of repeated learning (repeated acquisition) and performance. The proposed experiments seek, first, to determine using drug discrimination and receptor autoradiography procedures, the nature of Pb- induced changes in NMDA and MK-801 sensitivity at the level of the whole animal, any correspondence between sensitivity changes and NMDA receptor complex changes, and the conditions under which sensitivity changes occur, including the role of developmental period of exposure (including postnatal, postweaning and adult), associated blood and brain Pb levels, and the importance of a prior behavioral history of drug discrimination. Using a multiple schedule of repeated acquisition (learning) and performance combined with receptor autoradiography, the proposal also seeks to further explore the role of Pb-induced changes in the NMDA receptor complex to Pb-induced learning impairments, by determining whether other noncompetitive antagonist effects on this baseline are also attenuated by Pb exposure, whether such attenuation also occurs in response to competitive NMDA antagonists, and whether subchronic noncompetitive NMDA antagonist administration in normal untreated rats produces a pattern of learning impairments that mimics that produced by Pb exposure per se. Taken together, these experiments will yield a more precise understanding of the scope of Pb-induced changes in NMDA receptor complex function at the level of the whole animal, any receptor basis for such effects, and an increased understanding of the extent to which these effects have clinical significance for the behavioral toxicity of lead, particularly for learning impairments.

最近发表的细胞和生化研究表明PB 暴露可能会通过抑制作用损害学习和记忆功能 对NMDA受体复合物的作用。 这个基于NMDA的概念 PB行为毒性的机制具有吸引力，因为：a） 可以考虑对PB暴露的行为毒性 发展早期或在职业暴露条件下；少量 可以解释学习亲戚的PB的优惠脆弱性 到性能功能； c）与 PB在海马（NMDA受体区域）中的优先积累 密度; d）它将为认知缺陷提供一种机制 缺乏定义的形态病变。 这样的论点 但是，信任或临床意义要求基于NMDA 敏感性在行为层面和/或化合物作用的敏感性会改变 在NMDA受体复合物可以改变PB诱导的学习变化。 该实验室的新数据支持争夺，包括 准确性障碍的衰减和增强 非竞争力NMDA拮抗剂MK-801和谷氨酸的影响 相对于多个的对照组，PB暴露大鼠中的激动剂NMDA 重复学习的时间表（重复获得）和表现。 提出的实验首先寻求确定使用药物 歧视和受体放射自显影程序，PB-的性质 在整个水平上诱导NMDA和MK-801灵敏度的变化 动物，灵敏度变化与NMDA受体之间的任何对应关系 复杂的变化以及灵敏度变化的条件 发生，包括暴露期的作用（包括 出生后，断奶后和成人），相关的血液和脑PB水平， 以及先前的药物歧视行为史的重要性。 使用重复收购的多个时间表（学习）和 性能与受体放射自显影相结合，该提案也 试图进一步探索PB诱导的NMDA变化的作用 通过确定 其他非竞争性拮抗剂对该基线的影响是否也是 通过PB暴露减弱，是否也发生这种衰减 对竞争性NMDA拮抗剂的响应，以及亚基 正常未处理大鼠的非竞争性NMDA拮抗剂给药 产生一种学习障碍的模式，这些模型是由 PB本身。 综上所述，这些实验将产生更多 对PB诱导的NMDA受体变化范围的精确理解 整个动物水平的复杂功能，任何受体的基础 这种影响，以及对这些影响的程度增加 影响对铅的行为毒性具有临床意义， 特别是用于学习障碍。