AbstractGlial cell line‐derived neurotrophic factor (GDNF) has been shown to be neuroprotective in animal models of the dopamine deficiency in Parkinson's disease. To examine the role of the extracellular signal‐regulated kinases 1 and 2 (ERK1/2) in this process, we infused a single dose of GDNF into the striatum of mice and analyzed the effect on ERK1/2 by immunohistochemistry and Western blot analysis. GDNF caused an increase in the phosphorylation of ERK1/2 both in the striatum and in tyrosine hydroxylase‐positive neurons in the substantia nigra. In the striatum, the increase in ERK1/2 phosphorylation was evident by 3 hr and persisted for at least 7 days, whereas, in the substantia nigra, an increase in phosphorylated ERK1/2 was first evident at 24 hr and persisted for at least 7 days. The increase in phosphorylated ERK1/2 was maximal at 0.45 μg GDNF at the time points examined. GDNF also protected dopamine terminals against the loss of tyrosine hydroxylase immunoreactivity normally associated with the intrastriatal administration of 6‐hydroxydopamine (0.5 μg/0.5 μl). However, this was observed only at a much higher dose of GDNF, 4.5 μg. Thus, our results suggest that the ability of GDNF to protect dopamine neurons cannot be explained solely in terms of its influence on ERK1/2 and that the role of other signaling pathways should be explored. © 2008 Wiley‐Liss, Inc.