Our study was designed to determine whether intrastriatal administration of glial cell line-derived neurotrophic factor (GDNF) can attenuate the behavioral effects and injury to the mesostriatal dopaminergic system caused by 6-hydroxydopamine (6-OHDA). Four groups of rats received a series of four intrastriatal injections of vehicle or one of three doses of GDNF (0.1, 1 or 10 micrograms per injection) on days 1,3,5 and 8. On day 4 the animals received a single, intrastriatal injection of 25 micrograms 6-OHDA. Treatment with GDNF significantly reduced the development of amphetamine-induced rotation, and the dose of 1 microgram per injection appeared to be the most effective. The group treated with this dose had significantly greater preservation of tyrosine hydroxylase-immunoreactive (TH-IR) fibers adjacent to the injection site in the striatum and significantly greater preservation of Nissl-stained and TH-IR neurons in the substantia nigra pars compacta (SNpc).