Glial cell line-derived neurotrophic factor (
GDNF) improves motor dysfunction associated with aging in rats and non-human primates, in animal models of
Parkinson's disease, and may improve motoric function in patients with advanced
Parkinson's disease. These improvements are associated with increased
dopamine function in the nigrostriatal system, but the molecular events associated with this increase are unknown. In these studies, 100 micro g of
GDNF was injected into the striatum of normal aged (24-month-old) male Fischer 344 rats. The
protein levels and phosphorylation of TH, ERK1/2, and related
proteins were determined by blot-immunolabeling of striatum and substantia nigra harvested 30 days after injection. In
GDNF-treated rats, TH phosphorylation at Ser31 increased approximately 40% in striatum and approximately 250% in the substantia nigra. In the substantia nigra, there was a significant increase in ERK1 phosphorylation. In striatum, there was a significant increase in ERK2 phosphorylation. Microdialysis studies in striatum showed that both
amphetamine- and
potassium-evoked
dopamine release in
GDNF recipients were significantly increased. These data show that
GDNF-induced increases in
dopamine function are associated with a sustained increase in TH phosphorylation at Ser31, which is greatest in the substantia nigra and maintained for at least one month following a single striatal administration of
GDNF. These findings, taken from the nigrostriatal system of normal aged rats, may help explain the long lasting effects of
GDNF on
dopamine function and prior studies supporting that a major effect of
GDNF involves its effects on
dopamine storage and somatodendritic release of
dopamine in the substantia nigra.