In order to examine the possible role of rat brain glutathione depletion by diethyl maleate (DEM) in the potentiation of 6-hydroxydopamine (6-OHDA) neurotoxicity, the relationships between both effects were evaluated using the circling behavior test (CBT), and determining striatal glutathione S-transferase (GST)-specific activity. There were significant differences between the two studied groups: 6-OHDA and DEM + 6-OHDA lesioned animals in striatal glutathione (GSH) concentration at the moment of the lesion with 6-OHDA and also at the end of the experiment (30 d after 6-OHDA lesion). The circling behavior test following the administration of amphetamine was qualitatively different between both groups of simple- and double-damaged animals. In accordance with our results, DEM injury makes the animals more susceptible to brain-oxidative damage by 6-OHDA, which can indicate that in the double-damaged animal group, DEM could induce potentiation of the toxicity through striatal glutathione depletion.