TRIADIMEFON AND TRIADIMENOL - EFFECTS ON MONOAMINE UPTAKE AND RELEASE

Acute administration of the agricultural fungicide triadimefon produce d a neurotoxic syndrome in rats characterized by increased motor activ ity, stereotyped behaviors, and altered monoamine metabolism, Triadime nol, a metabolite of triadimefon in mammals, plants, and soil, also in creased motor activity in rodents, To test the hypothesis that triadim efon and triadimenol are indirect-acting dopamine agonists, the presen t studies examined their abilities to inhibit monoamine uptake, bind t o the dopamine transporter, and stimulate dopamine efflux in rat brain tissue, in vitro. Both triazoles inhibited the uptake of dopamine in striatal synaptosomal preparations. Triadimefon was 100-fold less pote nt than GBR12909, a prototypical inhibitor of dopamine uptake (IC50 = 4.7 mu M vs, 37.2 nM, respectively), and triadimenol was about three-f old less potent than triadimefon, Triadimefon also weakly inhibited th e uptake of norepinephrine in cortical synaptosomes IC50 = 22.4 mu M), but neither compound blocked the uptake of serotonin in cortical syna ptosomes (IC50s > 100 mu M). Triadimefon and triadimenol had similar a ffinity for [H-3]mazindol binding sites on the dopamine transporter (I C50s approximate to 1-1.5 mu M, only two- to three-fold greater than G BR12909). Neither triadimefon nor triadimenol (0.01-100 mu M) increase d basal efflux of [H-3]DA that had been preloaded into striatal minces in vitro. An unexpected result was that GBR12909 (10 mu M) increased basal efflux of [H-3]DA by 71%, suggesting that this compound has DA r eleasing properties. These data suggest that increased synaptic concen trations of dopamine due to inhibition of dopamine uptake may play an important role in the neurobehavioral effects of triadimefon and triad imenol. (C) 1996 Academic Press, Inc.