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Parkinson's disease (PD) is characterized by a bilateral progressive degeneration of nigrostriatal dopaminergic neurons. Among several toxin-induced animal models of PD, a single intrastriatal injection of 6-hydroxydopamine (6-OHDA) has been reported to provoke a retrograde degeneration of nigral dopaminergic neurons and may reflect an early stage of PD. However, the lack of a progressive neuronal loss in those acute models limits the suitability for the assessment of neuroprotective therapeutics. Therefore, we investigated if repeated microinjections of 6-OHDA into the striatum of mice may generate a subchronic model with progressive degeneration. In contrast to acute bilateral microinjections of 8 microg 6-OHDA, repeated daily intrastriatal applications for 5 d provoked a moderate, but significant loss of nigral neurons. However, a longer treatment over 7 d failed to cause a more marked degeneration than observed after 5 d. Motor performance was unaltered after single and repeated treatments, except of a slight cataleptic behavior and shortened stride-length performance in mice treated over 7 d. The present data show for the first time that daily intrastriatal injections of 6-OHDA over 5 d can enhance the nigrostriatal neurodegeneration in mice. However, the extent of the neuronal loss was moderate and the technical expense limits the utility as a subchronic model.