PCB-induced inhibition of the vesicular monoamine transporter predicts reductions in synaptosomal dopamine content
PCB-induced inhibition of the vesicular monoamine transporter predicts reductions in synaptosomal dopamine content
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DOI：
10.1093/toxsci/kfh153
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发表时间：
2004-08-01
影响因子：
3.8
通讯作者：
Seegal, RF
中科院分区：
文献类型：
--
作者：
Bemis, JC;Seegal, RF
多氯联苯混合物和单独的非共面多氯联苯同系物都能降低培养细胞以及发育中和成年实验动物大脑中的多巴胺浓度。这些减少可能涉及抑制多巴胺转运蛋白（DAT）和囊泡单胺转运蛋白（VMAT），分别负责细胞外DA的摄取和神经末梢胞质DA包装成突触囊泡。然而，每种单胺转运蛋白对PCB诱导的组织DA减少的相对贡献尚未确定。因此，我们暴露成年大鼠纹状体突触体个别PCB同系物，PCB或已知的单胺转运蛋白抑制剂的商业混合物;测量突触体DA;和媒体DA和3，4-二羟基苯乙酸（DOPAC）的浓度相关的这些变化。多氯联苯诱导的培养基DA浓度升高不足以解释组织DA的减少，因为已知的DAT抑制剂使培养基DA升高的程度比多氯联苯大得多，但诱导组织DA浓度类似的降低。另一方面，PCB诱导的DOPAC升高，反映了神经末梢胞质DA的增加，足以解释组织DA的减少，因为已知的VMAT抑制剂升高DOPAC并降低组织DA至与PCB相似的程度。两者合计，这些结果表明，DOPAC的升高，反映了神经末梢胞质DA的增加，由于VMAT抑制，而不是在介质DA的升高，由于DAT抑制，是主要负责观察到的组织DA含量的下降。
Both Aroclor mixtures and individual non-coplanar polychlorinated biphenyl (PCB) congeners reduce dopamine (DA) concentrations in cells in culture and in the brains of developing and adult laboratory animals. These reductions may involve inhibition of the dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT) responsible, respectively, for the uptake of extracellular DA and the packaging of nerve terminal cytosolic DA into synaptic vesicles. However, the relative contribution of each monoamine transporter to the PCB-induced reductions in tissue DA has not been determined. Accordingly, we exposed striatal synaptosomes from adult rats to individual PCB congeners, a commercial mixture of PCBs or known monoamine transporter inhibitors; measured synaptosomal DA; and related these changes to media DA and concentrations of 3,4-dihydroxyphenylacetic (DOPAC). PCB-induced elevations in media DA concentrations are not sufficient to explain the reductions in tissue DA because known DAT inhibitors elevate media DA to a much greater extent than PCBs and yet induce similar decreases in tissue DA concentrations. On the other hand, PCB-induced elevations in DOPAC, reflective of increases in nerve terminal cytosolic DA, are sufficient to explain the reductions in tissue DA, because a known VMAT inhibitor elevates DOPAC and reduces tissue DA to an extent similar to that seen with PCBs. Taken together, these results suggest that elevations in DOPAC, reflective of increases in nerve terminal cytosolic DA due to VMAT inhibition, rather than elevations in media DA due to DAT inhibition, are largely responsible for the observed decreases in tissue DA content.