In Vivo Effects of Deltamethrin on Dopamine Neurochemistry and the Role of Augmented Neurotransmitter Release

Neurochemical analyses of dopamine, consistent with the development of parkinsonism, were performed in C57BL6 male mice. Mice were treated by intraperitoneal injection, three times over a 2-week period with 6 mg/kg deltamethrin alone or in combination with a single treatment of 20 mg/kg of the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP). In ex vivo synaptosomes prepared from treated mice, deltamethrin caused a 70% increase in maximal dopamine uptake, which would be consistent with increased dopamine outflow in vivo and suggested an up-regulation in dopamine transporter expression. In contrast, MPTP treatment had little effect on dopamine transport but it reversed the deltamethrin-induced increase in Vmax when given in combination. Potent effects of deltamethrin on dopamine release were confirmed in vitro, where deltamethrin had an EC50 of 48 nM for enhancing veratridine-stimulated dopamine release from preloaded striatal synaptosomes. Under similar experimental conditions, deltamethrin had an EC50 for enhancing glutamate release of 412 nM and an EC50 for enhancing serotonin release of 117 nM. Thus, the dopaminergic nerve terminals of the striatum were more sensitive to pyrethroid than those of other neurotransmitter types, and loss of dopamine from striatal terminals is a cardinal sign of Parkinsonʹs disease. The augmented release of dopamine and glutamate in vivo could underlie deltamethrin-induced neuronal insult, since elevated levels of these neurotransmitters are known to be neurotoxic. However, at the dose and assessment times used in this study, dopamine and DOPAC levels were not significantly affected by deltamethrin, although there was a small increase in the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), consistent with increased turnover of dopamine in vivo. In accord with previous studies, MPTP alone decreased levels of both dopamine and DOPAC. When coapplied, MPTP reversed the small increase in DOPAC caused by deltamethrin, perhaps indicating greater toxicity in the double-treatment group. Higher doses or longer exposure times would be expected to yield greater effects of deltamethrin on dopamine content in the nigrostriatum.