Triadimefon and triadimenol: Effects on monoamine uptake and release

Acute administration of the agricultural fungicide triadimefon produced a neurotoxic syndrome in rats characterized by increased motor activity, stereotyped behaviors, and altered monoamine metabolism. Triadimenol, a metabolite of triadimefon in mammals, plants, and soil, also increased motor activity in rodents. To test the hypothesis that triadimefon and triadimenol are indirect-acting dopamine agonists, the present studies examined their abilities to inhibit monoamine uptake, bind to 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 potent than GBR12909, a prototypical inhibitor of dopamine uptake (IC50 = 4.7 μM vs. 37.2 nM, respectively), and triadimenol was about threefold less potent than triadimefon. Triadimefon also weakly inhibited the uptake of norepinephrine in cortical synaptosomes (IC50 = 22.4 μM), but neither compound blocked the uptake of serotonin in cortical synaptosomes (IC50s > 100 μM). Triadimefon and triadimenol had similar affinity for [³H]mazindol binding sites on the dopamine transporter (IC50s ~ 1-1.5 μM, only two- to threefold greater than GBR12909). Neither triadimefon nor triadimenol (0.01-100 μM) increased basal efflux of [³H]DA that had been preloaded into striatal minces in vitro. An unexpected result was that GBR12909 (10 μM) increased basal efflux of [³H]DA by 71%, suggesting that this compound has DA releasing properties. These data suggest that increased synaptic concentrations of dopamine due to inhibition of dopamine uptake may play an important role in the neurobehavioral effects of triadimefon and triadimenol.