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The goal of this study was to examine the topological specificity of methamphetamine-induced activation of the immediate-early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6-OHDA rats. Lower levels of methamphetamine-induced FLI in the striatum and GP on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine-induced rotation. In the striatum, a similar tendency could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and SNr on both sides in the 6-OHDA rats. Intrastriatal grafts had little influence on Zif268 expression in these two regions. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following methamphetamine in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-specific and region-specific functions in the basal ganglia nuclei. Synapse 62: 920-926, 2008. V