Chronic effects of single intrastriatal injections of 6-hydroxydopamine or 1-methyl-4-phenylpyridinium studied by microdialysis in freely moving rats

Abstract

Extracellular dopamine (DA) and its main cerebral metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by bilateral striatal microdialysis in rats at different times (2, 7, 15 and 60 days) after unilateral administration into the right striatum of 1-methyl-4-phenylpyridinium ion (MPP +) or 6-hydroxydopamine (6-OHDA). In both cases the decrease in extracellular dopamine did not exceed 40% of control values. The response of DOPAC and HVA depended on the treatment: MPP + caused a marked acute decrease in the dopamine metabolites but allowed a progressive recovery that was very evident after 60 days; 6-OHDA caused a progressive decrease in the dopamine metabolites throughout the two months of the study. Tyrosine hydroxylase immunostaining revealed severe neuronal loss in substantia nigra two months after striatal administration of 6-OHDA, whereas no significant neuronal loss was found at the same time after MPP + administration. A bilateral challenge infusion of MPP + through the microdialysis probe was used to assess the dopaminergic capacity of both striata: at all the times studied there was a sharp depletion of DA on the non-lesioned side; both MPP +- and 6-OHDA-treated striata were unresponsive after a short time (2 days); after 2 months the response in MPP +-lesioned rats was similar on both sides, whereas 6-OHDA-lesioned striata were still unresponsive to MPP +. In rats, then, the effects of MPP + could be partly reversed whereas the effects of 6-OHDA were not. These results suggest that neurotoxins causing striatal dopamine loss may act through different mechanisms, which could be significant for the etiopathogenic development of Parkinson's disease.