ToxSci Advance Access published online on April 28, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh153
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 School of Public Health, University at Albany, Box 509, Albany, NY 12201-0509
* To whom correspondence should be addressed. E-mail: seegal{at}wadsworth.org.
Both Aroclor mixtures and individual non-coplanar polychlorinated biphenyl (PCB) congeners reduce dopamine (DA) concentrations in cells in culture and 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.
Accepted April 13, 2004
Neurotoxicology
PCB-Induced Inhibition of the Vesicular Monoamine Transporter Predicts Reductions in Synaptosomal Dopamine Content
2 New York State Department of Health, Wadsworth Center, Box 509, Albany, NY 12201-0509; School of Public Health, University at Albany, Box 509, Albany, NY 12201-0509
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