BEHAVIORAL TOXICITY OF LEAD--A PHARMACOLOGICAL ANALYSIS

铅的行为毒性--药理学分析

• 批准号: 2153906
• 负责人: Deborah A Cory-Slechta
• 金额: $ 28.69万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2153906
• 关键词: autoradiography; behavior; behavior disorders; behavior test; cholinergic receptors; densitometry; dopamine receptor; drug interactions; laboratory rat; lead poisoning; muscarinic receptor; neurotoxins; nicotinic receptors; receptor binding; receptor sensitivity; scintillation spectrometry; sensory discrimination; statistics /biometry; stimulant /agonist; tissue /cell culture

Undue lead (Pb) exposure remains one of the most pressing pediatric environmental health problems of this country, and yet the neurobiological basis of its behavioral toxicity remains unknown. Over the past 2 years, this application sought to confirm, using drug discrimination (DD) and receptor binding studies, the then prevailing hypothesis based on d-amphetamine studies that Pb exposure resulted in a functional dopaminergic (DA) subsensitivity which could underlie it's behavioral manifestations. However, our DD and receptor binding studies, using selective D1 and D2 agonists rather than d-amphetamine, revealed a functional DA supersensitivity which may be related to DA receptors in the nucleus accumbens, and which appears to differ with respect to D1 receptor involvement in postnatal vs. postweaning exposures. One postulated explanation for the this pattern of outcomes that is also consistent with previously reported d-amphetamine subsensitivity, is that these effects are achieved through inhibitory autoreceptor agonism. This renewal application relies primarily on DD procedures and receptor binding assays to first qualitatively confirm these observations in light of some gaps in our initial findings, to then further characterize the nature of this DA supersensitivity and finally to pursue hypothesis relating to nucleus accumbens as a site of these effects and inhibitory autoreceptor agonism as their basis. DD studies will be used to: qualitatively confirm these initial observations, determine whether they represent a direct effect on DA systems or occur via neurotransmitter interactions, whether D1 supersensitivity is a direct effect or results from D1/D2 receptor interactions, the extent to which D2 supersensitivity includes both autoreceptor and postsynaptic receptor components, whether a functional reuptake blockade subsensitivity consistent with autoreceptor agonism occurs with d-amphetamine and GBR12909 drug stimuli, the extent to which Pb-induced DA supersensitivity is mimicked by chronic autoreceptor agonism and is reversed by chronic autoreceptor antagonism, and adult susceptibility. Receptor binding studies, to be carried out concurrently with DD studies, will provide specific information with respect to the time-course of nucleus accumbens and striatal Bmax changes and their correspondence to DD sensitivity changes. The application also proposes a time-course assessment of Pb-induced changes in DA turnover and DA levels to provide information relevant to the autoreceptor agonism basis of such effect, and the incorporation of two additional behavioral baselines to determine if Pb-induced DA supersensitivity is a generalized behavioral supersensitivity. It is the more precise understanding of the nature and basis of Pb-induced DA supersensitivity to be achieved by these proposed studies that will permit the design of future experiments that directly examine the relationships between DA changes and the behavioral effects of Pb, experiments which will determine the importance of Pb-induced changes in DA systems as a neurobiological basis of Pb- induced behavioral toxicity.

不适当的铅（PB）暴露仍然是最紧迫的小儿之一 这个国家的环境健康问题，但 其行为毒性的神经生物学基础仍然未知。 超过 在过去的两年中，该申请试图使用药物确认 歧视（DD）和受体结合研究，当时流行 基于D-苯丙胺研究的假设，即PB暴露导致 功能性多巴胺能（DA）降低，可能是它的基础 行为表现。 但是，我们的DD和受体结合研究， 使用选择性D1和D2激动剂而不是D-苯丙胺，揭示了 功能性DA超敏反应，可能与DA受体有关 伏隔核，并且似乎相对于D1有所不同 受体参与产后与断奶后暴露。 一 对这种结果模式的假定解释也是如此 与先前报道的D-苯丙胺降低性一致的是 这些作用是通过抑制性自身受体激动剂来实现的。 这 更新应用主要依赖于DD程序和受体 绑定测定首先定性地确认这些观察结果 在我们的初始发现中的一些差距，然后进一步表征 这种超敏的性质，最后追求假设 与伏隔核作为这些作用的部位和抑制作用有关 自身受体激动剂作为其基础。 DD研究将用于： 定性确认这些初始观察结果，确定它们是否 代表对DA系统的直接影响或通过神经递质发生 相互作用，D1超敏性是直接效应还是结果 从D1/D2受体相互作用，D2超敏的程度 包括自身受体和突触后受体成分，是否包括 与 自身受体激动剂发生在D-苯丙胺和GBR12909药物刺激中发生， 慢性模仿PB诱导的DA超敏反应的程度 自身受体激动剂，并被慢性自身受体拮抗作用逆转， 和成人敏感性。 受体结合研究，进行 与DD研究同时将提供特定信息 尊重伏隔核和纹状体Bmax的时间顺序变化 以及它们与DD敏感性的对应。 也是该应用程序 提出了PB诱导的DA周转变化的时间课程评估 和DA级别提供与自动受体激动剂相关的信息 这种效果的基础，并纳入了两个其他行为 基准确定PB诱导的DA超敏性是否是广义的 行为超敏反应。 这是对 PB引起的DA超敏反应的性质和基础 这些提出的研究将允许设计未来的实验 直接研究了DA变化与 PB的行为效应，将决定重要性的实验 PB诱导的DA系统的变化是Pb-的神经生物学基础 诱导行为毒性。