BEHAVIORAL TOXICITY OF LEAD--PHARMACOLOGICAL ANALYSIS

该提案旨在检验铅（Pb）暴露导致 功能性多巴胺（DA）不敏感。 这个假设是基于 两个数据来源：1）实验表明，铅暴露大鼠 需要比对照组更高剂量的D-安非他明来区分药物 药物辨别（DD）范例中的生理盐水; 2）多份报告， 铅暴露的生物体表现出减弱的影响，d-安非他明在一个 各种行为模式。 然而，这些研究提供了几个 也有其他的解释。 这个问题还有待解决 然而，尽管有广泛的机械影响，但肯定是如此。 我们 我建议在训练过辨别能力的动物身上检验这一假设 来自盐水的DA D1激动剂或DA D2激动剂，使用标准的2- 杠杆DD范式。 选择性D1和D2受体配体的使用， 比具有混合性质的化合物，如安非他明，预计 提供任何功能性DA范围的精确信息 不敏感，以及它的确切性质。 以前的工作表明， 铅暴露的关键时期，这些多巴胺能效应， 产后的 本应用程序将比较早期发育铅暴露 根据对比证据， 这表明易感性延伸到成年动物。 的 在铅暴露动物中改变多巴胺能DD性能的可能性 可能是由于辨别能力的普遍损害造成的， 通过使用胆碱能DD进行评价：由于假定铅暴露 为了导致胆碱能超敏反应，所产生的DD效应应该 与DA激动剂观察到的方向相反。 最后 铅诱导的DA亚敏感性在多大程度上可以通过行为调节 将通过比较DA DD剂量效应函数与 在其他行为基线上获得的那些，特别是，固定的- 食物强化的间隔时间表和延迟交替范式。 从这些实验中，我们期望获得一个更全面， 铅诱导的DA亚敏感性的综合评估，可作为 未来实验的基础，旨在直接评估他们的 与铅诱导的行为毒性有关。

This proposal seeks to test the hypothesis that lead (Pb) exposure results in a functional dopaminergic (DA) subsensitivity. This hypothesis is based on two sources of data: 1) experiments indicating that Pb-exposed rats require higher doses of d-amphetamine than controls to distinguish the drug from saline in drug discrimination (DD) paradigms; 2) multiple reports that Pb-exposed organisms exhibit attenuated effects of d-amphetamine in a variety of behavioral paradigms. These studies, however, offer several alternative explanations as well. The question has yet to be resolved definitively, however, despite wide-ranging mechanistic implications. We propose to examine this hypothesis in animals trained to discriminate either a DA D1 agonist, or a DA D2 agonist from saline, using a standard 2- lever DD paradigm. The use of selective D1 and D2 receptor ligands, rather than a compound with mixed properties such as amphetamine, is expected to provide precise information on the extent of any functional DA subsensitivity, as well as it's exact nature. Previous work suggests that critical period of Pb exposure for these dopaminergic effects to be postnatal. This application will compare early developmental Pb exposures to those initiated later in development, in light of contrasting evidence which indicates that susceptibility extends t adult animals. The possibility that altered dopaminergic DD performance in Pb-exposed animals may result from a generalized impairment of discriminative capacity will be evaluated by using a cholinergic DD: since Pb exposure has been postulated to result in cholinergic supersensitivity, the resulting DD effects should be opposite in direction to those observed with DA agonists. Finally, the extent to which Pb-induced DA subsensitivity can be modulated by behavioral context will be determined by comparing DA DD dose-effect functions to those obtained on other behavioral baselines, specifically, a Fixed- Interval schedule of food reinforcement and a delayed alternation paradigm. From these experiments, we expect to attain a more comprehensive, integrated assessment of Pb-induced DA subsensitivity which can serve as the basis for future experiments designed to directly evaluate their relationship to Pb-induced behavioral toxicity.