Bloomquist Jeffrey R, Barlow Rebecca L, Gillette Jeffrey S, Li Wen, Kirby Michael L
Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0319, USA.
Neurotoxicology. 2002 Oct;23(4-5):537-44. doi: 10.1016/s0161-813x(02)00031-1.
A degeneration of the nigrostriatal pathway is a primary component of Parkinson's disease (PD), and we have investigated the actions of insecticides on this pathway. For in vivo exposures, C57BL/6 mice were treated three times over a 2-week period with heptachlor, the pyrethroids deltamethrin and permethrin, or chlorpyrifos. One day after the last treatment, we observed that heptachlor and the pyrethroids increased maximal [3H]dopamine uptake in striatal synaptosomes from treated mice, with dose-dependent changes in Vmax displaying a bell-shaped curve. Western blot analysis confirmed increased levels of dopamine transporter (DAT) protein in the striatum of mice treated with heptachlor and permethrin. In contrast, we observed a small, but statistically significant decrease in dopamine uptake by 100 mg/kg chlorpyrifos. For heptachlor, doses that upregulated DAT expression had little or no effect on serotonin transport. Permethrin did cause an upregulation of serotonin transport, but required a 30-fold greater dose than that effective on dopamine uptake. Other evidence of specificity was found in transmitter release assays, where heptachlor and deltamethrin released dopamine from striatal terminals with greater potency than other transmitter types. These findings confirm that insecticides possess specificity for effects on striatal dopaminergic neurotransmission.
黑质纹状体通路的退化是帕金森病（PD）的主要组成部分，我们已经研究了杀虫剂对该通路的作用。对于体内暴露实验，C57BL/6小鼠在2周内用七氯、拟除虫菊酯溴氰菊酯和氯菊酯或毒死蜱处理3次。在最后一次处理后一天，我们观察到七氯和拟除虫菊酯增加了处理过的小鼠纹状体突触体中最大[3H]多巴胺摄取量，Vmax的剂量依赖性变化呈现钟形曲线。蛋白质印迹分析证实，用七氯和氯菊酯处理的小鼠纹状体中多巴胺转运体（DAT）蛋白水平升高。相比之下，我们观察到100mg/kg毒死蜱使多巴胺摄取量有小幅但具有统计学意义的下降。对于七氯，上调DAT表达的剂量对5-羟色胺转运几乎没有影响。氯菊酯确实导致了5-羟色胺转运上调，但所需剂量比影响多巴胺摄取的有效剂量大30倍。在递质释放试验中发现了其他特异性证据，其中七氯和溴氰菊酯从纹状体终末释放多巴胺的效力高于其他递质类型。这些发现证实杀虫剂对纹状体多巴胺能神经传递的影响具有特异性。
