Important mediators in the pathogenesis of Parkinson's disease are oxidative stress and excitotoxicity. Increased glutamate concentrations can be linked to both processes. Extracellular glutamate concentrations are mainly determined by an interplay between vesicular glutamate transporters (VGLUTs), glial high-affinity Na⁺/K⁺-dependent glutamate transporters (GLAST and GLT-1) and the cystine/glutamate antiporter. Using semi-quantitative Western blotting, we studied the expression levels of VGLUT1, VGLUT2, GLAST and GLT-1 in the striatum of rats at different survival times (3, 5 and 12 weeks) after unilateral 6-OHDA injection into the medial forebrain bundle (hemi-Parkinson rat model). The significant bilateral increase in GLT-1 expression that we observed at 3 and 12 weeks post-lesion, was translated into an increased reuptake activity, as revealed by ex vivo D-[3H]-aspartate reuptake studies in striatal synaptosomes. To determine the origin of the increased striatal expression level of VGLUT1 protein at 3 weeks post-lesion and decreased expression at 12 weeks, in situ hybridization experiments were performed to visualize VGLUT1 mRNA expression levels throughout the brain of hemi-Parkinson rats. Our data suggest that the earlier observations by Meshul et al. (1999) of a biphasic change in extracellular striatal glutamate levels after 6-OHDA injection into the medial forebrain bundle, with increases 1 month post-lesion and decreases 3 months post-lesion, might be explained by an interplay of changes in the expression/functioning of all glutamate transporter families. Modulation of one or more of these transporters might help to normalize the extracellular glutamate levels and prevent further excitotoxic and oxidative damage.