Neurogenesis is an ongoing process in the hippocampus and olfactory bulb of adult mammals, regulated in part by trophic factors. While glial cell line-derived neurotrophic factor (GDNF) is being directly delivered into the nigrostriatal system of the brain for the treatment of Parkinson's disease in clinical trials, little is known about its effects on cell genesis in the brain. Here, we investigated the effects of GDNF on progenitor cell proliferation and differentiation in two GDNF-responsive areas, the hippocampus and substantia nigra. GDNF (18 microg/day) was infused in the striatum of 2-month-old Sprague-Dawley rats for 28 days. New cells were identified by the nuclear incorporation of 5-bromo-2-deoxyuridine (BrdU) and analyzed by light and electron microscopic immunostaining and quantitative morphometric techniques. GDNF significantly increased cell proliferation in the hippocampus by 78% and in the substantia nigra by 52%. There was no evidence of neurogenesis in the substantia nigra, with new cells displaying glial features and none of the 1549 BrdU-positive cells co-labeled for the dopamine neuronal marker tyrosine hydroxylase (TH). Rather, GDNF upregulated TH in existing neurons, consistent with the restorative actions of this tropic factor. The hippocampus is a site that supports adult neurogenesis and new cells generated here were closely associated with granule cells in the dentate gyrus. Some were double labeled for the neuronal marker NeuN; others had features of astrocytes, the principal source of new adult neurons in the hippocampus. The effects of GDNF on the hippocampus are potentially important in memory and learning processes.