Neurotoxicity of the organochlorine insecticide heptachlor to murine striatal dopaminergic pathways.
Changes in biochemical status of nerve terminals in the corpus striatum, one of the primary brain regions affected in Parkinson's disease, were studied in groups of C57BL/6 mice treated by ip injection three times over a 2-week period with 3--100 mg/kg heptachlor. On average, the maximal rate of striatal dopamine uptake increased > 2-fold in mice treated at doses of 6 mg/kg heptachlor and 1.7-fold at 12 mg/kg heptachlor. Increases in maximal rate of striatal dopamine uptake were attributed to induction of the dopamine transporter (DAT) and a compensatory response to elevated synaptic levels of dopamine. Significant increase in V(max) of striatal DAT was not observed at doses > 12 mg/kg, which suggested that toxic effects of heptachlor epoxide may be responsible for loss of maximal dopamine uptake observed at higher doses of heptachlor. In support of this conclusion, polarigraphic measurements of basal synaptosomal respiration rates from mice treated with doses of heptachlor > 25 mg/kg indicated marked, dose-dependent depression of basal tissue respiration. At doses of 6 and 12 mg/kg heptachlor, which increased expression of striatal DAT, uptake of 5-hydroxytryptamine into cortical synaptosomes was unaffected. Thus, striatal dopaminergic nerve terminals were found to be differentially sensitive to heptachlor. This reduced sensitivity of serotonergic pathways was mirrored in the greater potency of heptachlor epoxide to cause release of dopamine from preloaded striatal synaptosomes in vitro compared to release of serotonin from cortical membranes. These results suggest that heptachlor, and perhaps other organochlorine insecticides, exert selective effects on striatal dopaminergic neurons and may play a role in the etiology of idiopathic Parkinson's disease.
Kirby
M L
ML
Department of Entomology, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
Barlow
R L
RL
Bloomquist
J R
JR
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006533:Heptachlor / Q000008:administration & dosage / Q000633:toxicity*; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D010101:Oxygen Consumption / Q000187:drug effects*; D011048:Polarography; D012680:Sensitivity and Specificity; D013574:Synaptosomes / Q000378:metabolism; D014316:Tritium
D007306:Insecticides; D018377:Neurotransmitter Agents; D014316:Tritium; D006533:Heptachlor; D010100:Oxygen; D004298:Dopamine