Evidence for monoaminergic involvement in triadimefon-induced hyperactivity

Abstract

Triadimefon is a triazole fungicide that produces hyperactivity in both mice and rats similar to that seen following administration of compounds with catecholaminergic activity (e.g., d-amphetamine). To determine whether the triadimefon-induced hyperactivity is due to an action on CNS catecholaminergic systems, we evaluated the effects of combined treatment of triadimefon with either the tyrosine hydroxylase inhibitor d,l-alpha-methyl-p-tyrosine methyl ester HCl (alpha MPT) or the amine depletor reserpine. Adult male Long-Evans hooded rats, approximately 70 days of age were used. Dosage-effect functions were determined for alpha MPT (0-200 mg/kg IP), reserpine (0-2.5 mg/kg IP), d-amphetamine (0-3 mg/kg IP), and methylphenidate (0-40 mg/kg IP). Motor activity was measured as photocell interruptions in figure-eight mazes. The interaction between triadimefon and alpha MPT was determined with the following groups: 1) vehicle control; 2) 200 mg/kg triadimefon PO; 3) 100 mg/kg alpha MPT; and 4) both alpha MPT and triadimefon. A similar design was used to determine the interaction between triadimefon and reserpine (0.62 mg/kg), alpha MPT and d-amphetamine (1.5 mg/kg), and reserpine and methylphenidate (5.0 mg/kg). In the first experiment alpha MPT did not block the increased motor activity produced by triadimefon (i.e., both triadimefon alone and alpha MPT in combination with triadimefon produced significant increases in motor activity). alpha MPT did, however, block d-amphetamine-induced hyperactivity. Since alpha MPT did not antagonize the effect of triadimefon, these data suggest that increased motor activity produced by triadimefon is not mediated through release of newly synthesized catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of the Model Organism Caenorhabditis elegans to Elucidate Neurotoxic and Behavioral Effects of Commercial Fungicides

“…One commonly used azole, flutriafol, has been associated with liver toxicity, reduced body weight of offspring and possible endocrine disruption of female fertility in rats [13,14]. Another azole, triadimefon, disrupts dopamine neurotransmission function in rats, with subsequent effects on the nigrostriatal system that governs behaviors like general locomotor activity, as well as stereotyped, repetitive behaviors [15]. One recent study demonstrated edema and necrosis of circular and longitudinal muscle layers in earthworms exposed to tebuconazole for 14 days [16].…”

Role of ionotropic glutamatergic receptors and nitric oxide in the effects of flutriafol, a triazole fungicide, on the <i>in vivo</i> striatal dopamine release

“…The effects of these substances on the dopaminergic system were described for the first time in late 1980s and early 1990s, with initial observations of neurotoxic effects of triadimefon on the motor activity (Crofton, 1996;Crofton et al, 1988Crofton et al, , 1989Moser and MacPhail, 1989;Walker et al, 1990). Several posterior studies, demonstrated that the behavioral effects produced by triadimefon were caused by changes in dopaminergic neurotransmission (Crofton, 1996;Hill et al, 2000;Ikaiddi et al, 1997;Reeves et al, 2003;Walker and Mailman, 1996).…”

Neurotoxic Effects of Triazole Fungicides on Nigrostriatal Dopaminergic Neurotransmission

“…Some possible targets for the alterations in dopaminergic neurotransmission induced by triadimefon are the mechanisms of synthesis, release, reuptake, and degradation of dopamine in nerve endings. To determine the possible neurochemical mechanism of action of tiradimefon to induce behavioral change, Crofton et al (1989) evaluated the effects of combined treatment of triadimefon with either a tyrosine hydroxylase inhibitor (D,L-alpha-methyl-p-tyrosine methyl ester, alpha MPT) or a depletor of catecholamine stores (reserpine). These authors observed that alpha-MPT did not block the increased motor activity produced by triadimefon, while reserpine reversed this effect.…”

“…So, it was observed that exposition to low doses of triadimefon (50-100 mg/kg) increased the frequency of locomotion and rearing in rats. Also, exposition to higher doses (200 mg/kg) of triadimefon induced highly stereotyped behaviors and self-mutilation (Crofton et al, 1988(Crofton et al, , 1989Perkins et al, 1991;Moser et al, 1995;Walker et al, 1990). It is known that changes in motor activity may occur as a result of neurochemical changes, specifically in the dopaminergic neurotransmission in the nigro-striatal pathway.…”

“…It is known that changes in motor activity may occur as a result of neurochemical changes, specifically in the dopaminergic neurotransmission in the nigro-striatal pathway. So, to verify the hypothesis that the triadimefon-induced behavioral effects can be due to an action on dopaminergic system, Crofton et al (1989) evaluated the effects of combined treatment of triadimefon with either an inhibitor of dopamine synthesis or a dopamine vesicle depletor (reserpine). These authors observed that reserpine partially blocked the increases in motor activity produced by triadimefon, confirming that the fungicide produces its effects acting on the dopaminergic terminal.…”