Insecticide-Mediated Neurochemical and Behavioral Changes as Possible Predisposing Environmental Factors in Idiopathic Parkinson's Disease

Epidemiological studies implicate pesticide exposure as a possible etiologic factor in idiopathic Parkinson's Disease, which results from degeneration of nigrostriatal neurons, along with reduced levels of the neurotransmitter, dopamine. Behavioral and neurochemical analyses in C57BL6 mice were performed following a subchronic dosing regime with the organochlorine insecticide heptachlor or the pyrethroid deltamethrin. Results were compared to those induced by the established parkinsonian neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At the end of the treatment period, mice were assessed for effects on behavior, as well as levels of striatal dopamine, nerve terminal respiration, and synaptosomal dopamine transport.

The primary behavioral effect of deltamethrin was incoordination, while heptachlor caused hyperexcitability and increased locomotion. The major neurochemical effect observed for both compounds was upregulation of the presynaptic dopamine transporter (DAT) by 70% and 100% for deltamethrin and heptachlor, respectively. The insecticides exerted only modest effects on striatal levels of dopamine and its metabolite, dihydroxyphenylacetic acid. However, doses of heptachlor higher than those which caused induction of DAT (e.g. greater than or equal to 25 mg/kg), when administered subchronically, were found to cause convulsions in some animals and caused marked, dose-dependent depression of basal striatal tissue respiration rates. No synergism was observed between the effects of insecticides and MPTP.

Enhanced transport was thought to be a compensatory effect from increased release of transmitters by the insecticides, in vivo. Striatal dopamine, GABA and glutamate nerve terminals were differentially sensitive to the releasing effects of heptachlor compared to cortical serotonin terminals, and responded in the following rank order of sensitivity: dopamine > GABA > glutamate > serotonin. Additional experiments to characterize the mechanism(s) by which cyclodienes facilitate release of neurotransmitters in synaptosomes demonstrated a lack of distinct Ca²⁺ component and no involvement of retrograde DAT activity, suggesting that released label was of vesicular origin, but did not require Ca²⁺. Insecticidal toxicants, such as organochlorines and pyrethroids, which augment dopamine release and increase the maximal rate of dopamine uptake, may inundate the cytosol of nigrostriatal neurons with high concentrations of free dopamine, which has been shown by other researchers to induce apoptosis and may thereby contribute to the development of Parkinson's disease.

Funding for this work was provided under grant number HHHREP 94-01 by the Hawaii Heptachlor Foundation, a non-profit organization. The Hawaii Heptachlor Foundation may be contacted at the following address: Ocean View Center PH#3, 707 Richards St., Honolulu, HI 96813.