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ToxSci Advance Access published online on October 5, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj005
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received May 3, 2005
Accepted September 19, 2005

Neurotoxicology

Acrylamide Inhibits Dopamine Uptake in Rat Striatal Synaptic Vesicles

Richard M. LoPachin 1*, David S. Barber 2, Deke He 1, and Soma Das 1

1 Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 E. 210th st., Bronx, NY 10467
2 Center for Environmental and Human Toxicology, University of Florida, Building 471, Mowry Rd., Gainesville, FL 32611-0885

* To whom correspondence should be addressed.
Richard M. LoPachin, E-mail: lopachin{at}aecom.yu.edu


  Abstract

Evidence suggests that acrylamide (ACR) neurotoxicity is mediated by decreased presynaptic neurotransmitter release. Defective release might involve disruption of neurotransmitter storage and, therefore, we determined the effects of in vivo and in vitro ACR exposure on 3H-dopamine (DA) transport into rat striatal synaptic vesicles. Results showed that vesicular DA uptake was decreased significantly in rats intoxicated at either 50 mg/kg/d x 5 days or 21 mg/kg/d x 21 days. ACR intoxication also was accompanied by a reduction in KCl-evoked synaptosomal DA release, although consistent changes in presynaptic membrane transport were not observed. Silver stain and immunoblot analyses suggested that reduced vesicular uptake was not due to nerve terminal degeneration or to a reduction in corresponding synaptic vesicle content. Nor did the in vivo presynaptic effects of ACR involve changes in synaptosomal glutathione concentrations. In vitro exposure of striatal vesicles showed that both ACR and two sulfhydryl reagents, N-ethylmaleimide (NEM) and iodoacetic acid (IAA), produced concentration-dependent decreases in 3H DA uptake. Although ACR was significantly less potent than either NEM or IAA, all three chemicals caused comparable maximal inhibitions of vesicular uptake. Kinetic analysis of DA uptake showed that in vitro exposure to either ACR or NEM decreased Vmax and increased Km. Determination of radiolabel efflux from 3H DA-loaded vesicles indicated that ACR did not affect neurotransmitter retention. These data suggest that ACR impaired neurotransmitter uptake into striatal synaptic vesicles, possibly by interacting with sulfhydryl groups on functionally relevant proteins. The resulting disruption of vesicular storage might play a role in ACR-induced synaptic toxicity.

Keywords: acrylamide; toxic axonopathy; nerve terminal; synaptic vesicles; neurotransmitter uptake; adduct formation.
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