Dithiocarbamate pesticides affect glutamate transport in brain synaptic vesicles

Dithiocarbamate compounds are widely used agricultural fungicides that disp lay low acute toxicity in mammals and that may become neurotoxic after prol onged exposure. Mancozeb, among other dithiocarbamates tested, proved to be the most potent (K-i = 0.27 mu M) at noncompetitively inhibiting the in vi tro ATP-dependent uptake of [H-3]glutamate in rat cortical vesicles. Furthe rmore, mancozeb partially (20%) inhibited the ATP-dependent uptake of [C-14 ]methylamine, used as an index for the vesicular transmembrane proton gradi ent (Delta pH), and evoked its efflux from organelles previously incubated with the H-3-labeted marker. Meanwhile, the vesicular uptake of (36)chlorid e(-) anions whose concentrations regulate the transmembrane potential gradi ent (Delta psi(SV)) was not impaired. The dithiocarbamate effects on the ve sicular transport of [H-3]glutamate thus appeared to involve mainly the Del ta pH gradient rather than the potential gradient. Dithiocarbamate metaboli tes, the potent neurotoxin carbon disulfide included, did not affect the up take process, thus implying the relevance for inhibition of the persistence , if any, of parent compounds in the brain. The present novel and potent in vitro interferences of selected dithiocarbamate pesticides with the vesicu lar transport of glutamate, if representative of in vivo alterations, may p lay some role in the probably complex origin of dithiocarbamate neurotoxici ty.