The effect of developmental exposure to the fungicide triadimefon on behavioral sensitization to triadimefon during adulthood

Abstract

Triadimefon (TDF) is a triazole fungicide that acts as an indirect dopamine (DA) agonist by binding to the dopamine transporter (DAT) and increasing levels of synaptic DA. Studies in this laboratory have found that repeated dosing with TDF in adult mice leads to the development and robust expression of behavioral sensitization, a response mediated by dopaminergic and glutamatergic neurotransmitter systems, and causing long-term changes in dopaminergic function. Few studies have focused on the potential for TDF to be a developmental neurotoxicant. As such, the objective of the present study was to determine whether postnatal exposure to TDF would permanently alter DA systems and thereby influence TDF-induced expression of behavioral sensitization during adulthood. Male C57BL/6 mice were dosed intraperitoneally (i.p.) with 25 mg/kg TDF (TDF25), or oil (veh) from postnatal day (PND) 8 to 21. At 8–9 weeks of age, mice were split into four groups and treated with 75 mg/kg TDF (TDF75) or vehicle twice a week for a total of seven injections, with locomotor activity measured immediately after each injection. After a 2-week withdrawal period, mice were further split into eight groups, and challenged with TDF75 or vehicle to test for the expression of behavioral sensitization. Postnatal TDF exposure attenuated both the induction and expression of TDF-induced vertical but not horizontal sensitization in adults. Postnatal TDF exposure also produced long-term decreases in basal striatal dihydroxyphenylacetic acid (DOPAC) levels and nucleus accumbens shell DAT binding. These results indicate for the first time that TDF may be considered an environmental risk factor for developmental dopaminergic neurotoxicity.