In vivo effects of deltamethrin on dopamine neurochemistry and the role ofaugmented neurotransmitter release

Neurochemical analyses of dopamine, consistent with the development of park insonism, were performed in C57BL6 male mice. Mice were treated by intraper itoneal injection, three times over a 2-week period with 6 mg/kg deltamethr in alone or in combination with a single treatment of 20 mg/kg of the parki nsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In ex vivo synaptosomes prepared from treated mice, deltamethrin caused a 70% increase in maximal dopamine uptake, which would be consistent with increas ed dopamine outflow in vivo and suggested an up-regulation in dopamine tran sporter expression. In contrast, MPTP treatment had little effect on dopami ne transport but it reversed the deltamethrin-induced increase in V-max whe n given in combination. potent effects of deltamethrin on dopamine release were confirmed in vitro, where deltamethrin had an EC50 of 48 nM for enhanc ing veratridine-stimulated dopamine release from preloaded striatal synapto somes. Under similar experimental conditions. deltamethrin had an EC50 for enhancing glutamate release of 412 nM and an EC50 for enhancing serotonin r elease of 117 nM. Thus, the dopaminergic nerve terminals of the striatum we re more sensitive to pyrethroid than those of other neurotransmitter types, and loss of dopamine from striatal terminals is a cardinal sign of Parkins on's disease. The augmented release of dopamine and glutamate in vivo could underlie deltamethrin-induced neuronal insult, since elevated levels of th ese neurotransmitters are known to be neurotoxic. However, at the dose and assessment times used in this study, dopamine and DOPAC levels were not sig nificantly affected by deltamethrin, although there was a small increase in the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), consistent with inc reased turnover of dopamine in vivo. In accord with previous studies, MPTP alone decreased levels of both dopamine and DOPAC. When co-applied, MPTP re versed the small increase in DOPAC caused by deltamethrin, perhaps indicati ng greater toxicity in the double-treatment group. Higher doses or longer e xposure times would be expected to yield greater effects of deltamethrin on dopamine content in the nigrostriatum. (C) 1999 Academic Press.