BEHAVIORAL TOXICITY OF LEAD--A PHARMACOLOGICAL ANALYSIS

描述：(改编自《调查者摘要》)高铅(铅)车身 负担仍然影响着近9%的美国儿童和一些地区40%的儿童 不发达国家。它与儿童认知缺陷的关系 对于年长的男性和女性，以及犯罪和攻击性，使其成为一种 比人们普遍认识到的更普遍的公共卫生问题。我们的 过去资助期的神经化学和行为研究表明 慢性断奶后铅似乎以中脑边缘多巴胺(DA)系统为目标， 根据在其末端投影区观察到的效果，原子核 伏隔草(NAC)。然而，NAC被认为是边缘-运动界面， 通过海马区谷氨酸能投射整合信息 前额叶皮质是众所周知的调节认知功能的两个区域。在 同时，铅还对谷氨酸能NMDA产生广泛的抑制作用 感受器。NMDA在前额叶皮质和NAC显示出抑制作用 增强非NMDAAMPA/海人藻酸兴奋性氨基酸受体的激活。 因此，拟议的研究验证了铅诱导的行为 中脑边缘系统的损伤和神经化学变化实际上源于 谷氨酸能神经元AMP/海人藻酸受体的优先激活 从海马体和前额叶皮质到NAC的投射。这一假设 预测海马区和前额叶谷氨酸能投射到NAC 在调节已知由铅改变的行为方面应该是关键的。特定的 因此，目标1和目标2将决定这些预测的断开 也会扰乱这些行为，而且是否优先激活AMPA能 这些投射可以模拟铅对正常大鼠的行为毒性，使用 受铅影响的两个行为基线：固定间隔性能和 一种重复的学习模式。《特定目标3》测试了相关的预测 这些投射区域中的AMPA拮抗剂应该逆转这些 铅引起的行为障碍。具体目标4试图确定 这些投射的优先AMPA能激活在正常情况下复制 大鼠NAc中诱发的DA溢出增加与铅和AMPA 拮抗剂可以逆转铅处理大鼠的这些增加。要确定 这些机制在多大程度上概括了人类铅暴露以及 在发育早期的暴露可能会加剧这些问题，具体目标2 4比较断奶前、断奶后和持续铅暴露的影响。 这些实验将极大地促进我们对控制的理解 海马区和前额叶投射对复杂操作认知行为的影响 电路和铅破坏它们的机制。他们将进一步定义 NMDA和AMPA/海人藻酸受体在这些投射中的作用比较 以及它们与DA系统的交互，允许理性的行为和 中脑边缘系统功能障碍的治疗方法。

DESCRIPTION: (Adapted from the Investigator's Abstract) Elevated lead (Pb) body burden still impacts almost 9% of U.S. children and >40% of children in some underdeveloped countries. Its association with cognitive deficits in children and in elderly men and women, and with delinquency and aggression, makes it a more pervasive public health problem than has generally been appreciated. Our neurochemical and behavioral studies over the past funding period show that chronic postweaning Pb appears to target the mesolimbic dopamine (DA) system, based on effects observed in its terminal projection region, the nucleus accumbens (NAC). NAC, however, is considered a limbic-motor interface, integrating information via glutamatergic projections from hippocampus and prefrontal cortex, two regions well known to mediate cognitive function. At the same time, Pb also produces a widespread inhibition of glutamatergic NMDA receptors. NMDA inhibition has been shown in prefrontal cortex and NAC to enhance activation of non-NMDA AMPA/kainate excitatory amino acid receptors. The proposed studies therefore test the hypothesis that Pb-induced behavioral impairments and neurochemical changes in mesolimbic systems actually derive from preferential AMP/kainate receptor activation of the glutamatergic projections from hippocampus and prefrontal cortex, to NAC. This hypothesis predicts that hippocampal and prefrontal glutamatergic projections to NAC should be critical in mediating behaviors known to be altered by Pb. Specific Aims 1 and 2 will thus determine whether disconnection of these projections also disrupts these behaviors, and whether preferential AMPAergic activation of these projections can mimic the behavioral toxicity of Pb in normal rats, using two behavioral baselines reliably altered by Pb: fixed interval performance and a repeated learning paradigm. Specific Aim 3 tests the associated prediction that AMPA antagonists in these projection regions should reverse these Pb-induced behavioral impairments. Specific Aim 4 seeks to determine whether preferential AMPAergic activation of these projections reproduces in normal rats the increases in evoked DA overflow in NAC associated with Pb, and if AMPA antagonists can reverse these increases in Pb-treated rats. To determine the extent to which these mechanisms generalize to human Pb exposure and whether they may be exacerbated by exposures earlier in development, Specific Aims 2 and 4 compare effects of preweaning, postweaning and continuous Pb exposures. These experiments will significantly advance our understanding of the control of complex operant cognitive behaviors by hippocampal and prefrontal projection circuits and the mechanisms by which Pb disrupts them. They will further define the comparative roles of NMDA and AMPA/kainate receptors in these projections and their interactions with DA systems, allowing rational behavioral and therapeutic approaches to mesolimbic system dysfunctions.