Glial cell-line derived neurotrophic factor (GDNF) gene therapy might offer new strategies for the treatment of Parkinson's disease (PD). GDNF is a potent dopaminergic (DA) neurotrophic factor. The effect of GDNF gene therapy was assessed using anatomical, behavioral, and neurochemical approaches. We examined the protective effect of increased striatal GDNF levels achieved by delivery of an adenoviral vector (Ad-) encoding human GDNF (Ad-GDNF). Animals were injected with Ad-GDNF prior to striatal lesion. Striatal DA concentration was measured by microdialysis. Animals receiving 6-hydroxydopamine (6-OHDA) only showed a significant decrease in rotation when compared to those receiving Ad-GDNF prior to the 6-OHDA neurotoxin. Under basal conditions, the Ad-GDNF group showed a significant (P < or = 0.05) increase (1880%) in DA concentration when compared to the 6-OHDA group. Amphetamine challenge induced a significantly (P < or = 0.05) higher release of DA in the Ad-GDNF group than in the 6-OHDA group. These findings show that long-term delivery of GDNF protein in the striatum provides significant cell, behavioral, and neurochemical protection.