BEHAVIORAL TOXICITY OF LEAD--A PHARMACOLOGICAL ANALYSIS

不适当的铅暴露仍然是儿童最紧迫的问题之一 这个国家的环境健康问题，然而 其行为毒性的神经生物学基础尚不清楚。完毕 在过去的2年里，这份申请寻求确认，使用药物 歧视(DD)和受体结合研究，当时盛行 基于d-苯丙胺研究的假设，铅暴露导致 一种功能性多巴胺能(DA)亚敏感，这可能是它的基础 行为表现。然而，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超敏反应可能与脑内DA受体有关 伏隔核，它似乎与d1不同 受体在出生后暴露与断奶后暴露之间的关系。一 对这种结果模式的假设解释也是 与之前报道的d-苯丙胺亚敏感一致 这些效应是通过抑制性自身受体激动剂实现的。这 续期申请主要依赖DD程序和受体 结合化验以首先定性地确认这些观察结果 我们最初的发现中的一些差距，然后进一步描述 这种DA超敏感性的本质及最终追寻假说 与伏隔核作为这些影响和抑制的部位有关的 以自身受体激动剂为基础。DD研究将用于： 定性地确认这些初步观察，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 交互作用，D1超敏感性是直接效应还是结果 从d1/d2受体的相互作用来看，d2的超敏感程度 包括自身受体和突触后受体成分，无论是 功能性再摄取阻断亚敏感符合 D-苯丙胺和GBR12909药物刺激会发生自体受体激动， 铅诱导的多巴胺超敏反应在多大程度上被慢性 自身受体激动，并被慢性自身受体拮抗逆转， 和成人的易感性。受体结合研究，有待进行 与DD研究同时进行，将提供以下具体信息 伏隔核与纹状体Bmax变化的时程关系 它们与DD敏感性的对应关系发生了变化。该应用程序还 提出了铅引起的DA周转变化的时程评估 和DA水平来提供与自身受体激动性相关的信息 这种效果的基础上，并加入了两个额外的行为 确定铅诱导的多巴胺超敏反应是否是一种全面性的基线 行为过敏症。它更准确地理解了 铅诱导的多巴胺超敏反应的性质和基础 这些拟议的研究将允许设计未来的实验 直接考察DA变化与 铅的行为效应，将决定其重要性的实验 铅引起的DA系统改变作为铅中毒的神经生物学基础 诱发的行为毒性。

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.