GABAERGIC INSECTICIDE TOXICOLOGY

长期目标是确定 作用于γ-氨基丁酸的杀虫剂的选择毒性 哺乳动物和昆虫的GABA受体。这是少校的目标 神经毒性杀虫剂作为阻断剂和激活剂， GABA门控氯离子通道。 超过50亿磅 在过去的50年里，渠道阻断剂一直被用于害虫控制 并且它们的氯含量范围为52- 73%。大通道 目前使用的阻断剂占杀虫剂市场的6%， 硫丹和林丹，这一市场份额将随着 新商业化的多卤代氟虫腈的用途。 的 诸如阿维菌素和莫昔克丁的活化剂也用于 作为杀虫剂和驱虫剂的数量不断增加。 更 具体来说，目标是提供毒理学概况和地图， 杀虫剂阻断剂位点和杀虫剂激活剂位点， 设计和使用高亲和力放射性配体（杀虫剂本身 或密切相关的模型化合物）和光亲和探针来研究 结合位点的相互作用和脑中的定位和氯离子 频道重点将放在发现之间的差异 哺乳动物和昆虫的GABA受体， 对杀虫剂的敏感性和对哺乳动物的安全性。 有关建议是 制备合适的放射性配体和光亲和探针， 将结合位点定位于脑区、受体亚单位和 哺乳动物氯离子通道中的特异性衍生氨基酸 （牛）和昆虫（果蝇）;化学实现这一目标 很大程度上来自于这个实验室的发现。 研究还 涉及大鼠小脑颗粒细胞在原代培养研究 完整细胞中的放射性配体结合和氯离子通量， 在体外和体内后小鼠脑切片中的放射性配体结合 暴露于未标记的毒物，以及来自Sf 9细胞的受体 用人GABA α受体亚单位的cDNA转染。

The long-term objective is to define the fundamental basis for the selective toxicity of insecticides acting at the gamma-aminobutyric acid (GABA) receptor of mammals and insects. This is the target of major neurotoxic insecticides acting as both blockers and activators of the GABA-gated chloride channel. More than 5,000,000,000 pounds of these channel blockers have been used for pest control in the past 50 years and they range in chlorine content from 52-73%. The major channel blockers used at present, representing 6% of the insecticide market, are endosulfan and lindane and this market share will increase with expanded use of the newly-commercialized polyhalogenated fipronil. The activators such as avermectin and moxidectin are also used in ever increasing quantities as insecticides and anthelmintics. More specifically, the goal is to provide toxicological profiles and maps for the insecticide blocker site and the insecticide activator site by designing and using high-affinity radioligands (the insecticide itself or a closely-related model compound) and photoaffinity probes to study binding site interactions and localization in the brain and chloride channel. Emphasis will be placed on the discovery of differences between the GABA receptors of mammals and insects that confer preferential sensitivity to insecticides and safety to mammals. The proposal is to prepare suitable radioligands and photoaffinity probes and use them to localize the binding sites as to brain region, receptor subunit and specific derivatized amino acid(s) in the chloride channel of mammals (bovine) and insects (Drosophila); the chemistry to achieve this end comes largely from discoveries in this laboratory. The research also involves rat cerebellar granule cells in primary culture to study radioligand binding and chloride flux in intact cells, localization of radioligand binding in mouse brain slices following in vitro and in vivo exposure to unlabeled toxicants, and receptors derived from Sf9 cells transfected with cDNs of human GABAa receptor subunits.