Kirby M L, Barlow R L, Bloomquist J R
Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
Toxicol Sci. 2001 May;61(1):100-6. doi: 10.1093/toxsci/61.1.100.
Changes in biochemical status of nerve terminals in the corpus striatum, one of the primary brain regions affected in Parkinson's disease, were studied in groups of C57BL/6 mice treated by ip injection three times over a 2-week period with 3--100 mg/kg heptachlor. On average, the maximal rate of striatal dopamine uptake increased > 2-fold in mice treated at doses of 6 mg/kg heptachlor and 1.7-fold at 12 mg/kg heptachlor. Increases in maximal rate of striatal dopamine uptake were attributed to induction of the dopamine transporter (DAT) and a compensatory response to elevated synaptic levels of dopamine. Significant increase in V(max) of striatal DAT was not observed at doses > 12 mg/kg, which suggested that toxic effects of heptachlor epoxide may be responsible for loss of maximal dopamine uptake observed at higher doses of heptachlor. In support of this conclusion, polarigraphic measurements of basal synaptosomal respiration rates from mice treated with doses of heptachlor > 25 mg/kg indicated marked, dose-dependent depression of basal tissue respiration. At doses of 6 and 12 mg/kg heptachlor, which increased expression of striatal DAT, uptake of 5-hydroxytryptamine into cortical synaptosomes was unaffected. Thus, striatal dopaminergic nerve terminals were found to be differentially sensitive to heptachlor. This reduced sensitivity of serotonergic pathways was mirrored in the greater potency of heptachlor epoxide to cause release of dopamine from preloaded striatal synaptosomes in vitro compared to release of serotonin from cortical membranes. These results suggest that heptachlor, and perhaps other organochlorine insecticides, exert selective effects on striatal dopaminergic neurons and may play a role in the etiology of idiopathic Parkinson's disease.
在帕金森病中受影响的主要脑区之一纹状体中，神经末梢的生化状态变化在C57BL/6小鼠组中进行了研究，这些小鼠在2周内通过腹腔注射给予3 - 100 mg/kg七氯，共注射三次。平均而言，在接受6 mg/kg七氯处理的小鼠中，纹状体多巴胺摄取的最大速率增加了2倍以上，在接受12 mg/kg七氯处理的小鼠中增加了1.7倍。纹状体多巴胺摄取最大速率的增加归因于多巴胺转运体（DAT）的诱导以及对多巴胺突触水平升高的代偿反应。在剂量> 12 mg/kg时未观察到纹状体DAT的V(max)显著增加，这表明七氯环氧化物的毒性作用可能是导致在较高剂量七氯下观察到的最大多巴胺摄取丧失的原因。支持这一结论的是，对接受剂量> 25 mg/kg七氯处理的小鼠进行的极谱法测量显示，基础突触体呼吸速率出现明显的剂量依赖性降低。在七氯剂量为6和12 mg/kg时，纹状体DAT的表达增加，但5-羟色胺向皮质突触体的摄取未受影响。因此，发现纹状体多巴胺能神经末梢对七氯的敏感性存在差异。与皮质膜中5-羟色胺的释放相比，七氯环氧化物在体外从预加载的纹状体突触体中释放多巴胺的效力更大，这反映了5-羟色胺能途径的敏感性降低。这些结果表明，七氯以及可能的其他有机氯杀虫剂对纹状体多巴胺能神经元发挥选择性作用，可能在特发性帕金森病的病因中起作用。
