ToxSci Advance Access originally published online on April 28, 2004
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Toxicological Sciences 80, 288-295 (2004)
Toxicological Sciences vol. 80 no. 2 © Society of Toxicology 2004; all rights reserved.
PCB-Induced Inhibition of the Vesicular Monoamine Transporter Predicts Reductions in Synaptosomal Dopamine Content
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* New York State Department of Health, Wadsworth Center, and School of Public Health, University at Albany, Box 509, Albany, New York 12201-0509
Received February 23, 2004; accepted April 13, 2004
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.
Key Words: polychlorinated biphenyls (PCBs); dopamine; synaptosomes; dopamine transporter (DAT); vesicular monoamine transporter (VMAT).
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