Diethyldithiocarbamate and disulfiram inhibit MPP + and dopamine uptake by striatal synaptosomes

Abstract

Diethyldithiocarbamate (DDC) was found to inhibit the uptake of both dopamine and 1-methyl-4-phenyl-pyridinium ion (MPP +, the putative toxic metabolite of the neurotoxicant MPTP) by striatal synaptosomes. Disulfiram, the corresponding disulfide of DDC, was effective at concentrations 1 000 times lower (10 −6 vs. 10 −3 M). Disulfiram, but not DDC, reacted very efficiently with synaptosomal protein thiols: both DDC- and disulfiram-induced uptake inhibition could be reversed by the thiol-reducing agent dithiothreitol. Two other thiol-reactive compounds, N-ethylmaleimide (NEM) and p-hydroxymercuribenzoate(PMB), also impaired the uptake of MPP + by striatal synaptosomes. PMB, which does not cross membranes, was even more potent than the lipophilic NEM in blocking MPP + uptake. These results suggest that (1) the effect of DDC may be mediated by disulfiram, (2) the uptake of MPP + and dopamine by striatal synaptosomes is dependent on the redox state of protein thiols, and (3) these protein thiols are located at the outer surface of synaptosomal membranes.