Triadimefon, a triazole fungicide, induces stereotyped behavior and alters monoamine metabolism in rats.

Triadimefon, a triazole fungicide, has been observed to increase locomotion and induce stereotyped behavior in rodents. The present experiments designed to characterize the stereotyped behavior induced by triadimefon used a computer-supported observational method, and tested the hypothesis that these observed effects involved central dopaminergic systems. Adult male and female Sprague-Dawley rats were injected with triadimefon (0, 50, 100, and 200 mg/kg) in corn oil (2 ml/kg ip) 4 hr prior to behavioral assessment. The two lowest doses of triadimefon increased the frequency of locomotion and rearing, while the highest dose induced highly stereotyped behaviors, including backward locomotion, circling, and head weaving. Immediately after behavioral testing, the rats were sacrificed, and the striata and olfactory tubercles, terminal fields of the nigrostriatal and mesolimbic dopamine systems, respectively, were removed. Steady-state concentrations of the monoamines dopamine and serotonin and their metabolites were determined by HPLC-EC. In independent experiments, the direct effects of triadimefon on dopamine (D1 and D2) receptor binding and dopamine-sensitive adenylate cyclase activity were assessed in vitro using rat striata. Dopamine concentrations were increased in olfactory tubercles, but decreased in striatum. Concentrations of 5-hydroxyindoleacetic acid (the major metabolite of serotonin) were increased only in striatum, and only in animals treated with 200 mg/kg triadimefon. In vitro, triadimefon neither competed with D1 or D2 dopaminergic radioligands nor affected dopamine-stimulated adenylate cyclase activity. Together these behavioral and biochemical data lend support to the hypothesis that triadimefon may have actions similar to those produced by indirect-acting dopamine agonists.