The tyramine-labelled vesicular transporter for dopamine: a putative target of pesticides and neurotoxins

Abstract

This study defined the ability of a large sample of heterogeneous pesticides and neurotoxins to interact with the [³H]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 [³H]tyramine binding, with K_i values ranging from 5 nM to 10 μM. ATP/Mg²⁺-dependent [³H]tyramine uptake to purified striatal synaptic vesicles was also inhibited by rotenone. Organophosphate and carbamate insecticides, and miscellaneous herbicides poorly antagonized [³H]tyramine binding, yielding K_i values exceeding 10 μM. 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 ≥ 6-hydroxydopamine > N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) > 1-methyl-4-pheny;-1,2,3,6-tetrahydropyridine (MPTP), with K_i values ranging from 35 nM to 3 μM. 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.