THE TYRAMINE-LABELED VESICULAR TRANSPORTER FOR DOPAMINE - A PUTATIVE TARGET OF PESTICIDES AND NEUROTOXINS

This study defined the ability of a large sample of heterogeneous pesticides and neurotoxins to interact with the [H-3]tyramine-labelled vesicular transporter of dopamine in rat striatum. Botanical (with rotenone as the most potent), and organochlorine (Kepone) insecticides, as well as fungicides (Zineb), as a whole, consistently inhibited [H-3]tyramine binding, with K-i values ranging from 5 nM to 10 mu M. ATP/Mg2+-dependent [H-3]tyramine uptake to purified striatal synaptic vesicles was also inhibited by rotenone. Organophosphate and carbamate insecticides, and miscellaneous herbicides poorly antagonized [H-3]tyramine binding, yielding K-i values exceeding 10 mu M. Several, though not all, of the best recognized central neurotoxins tested were major binding antagonists. Their rank order of potency was 1-methyl-4-phenylpyridinium ion (MPP(+)) > trimethyltin greater than or equal to 6-hydroxydopamine > N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) > 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with K-i values ranging from 35 nM to 3 mu M. Overall, the potent interaction of selected pesticides and chemicals with the vesicular transporter for dopamine, although, by itself, not synonymous with neurotoxicity, would argue for a likely impairment of transmitter homeostasis, or the putative formation of neurodegenerative toxin pools.