Striatal GDNF administration increases tyrosine hydroxylase phosphorylation in the rat striatum and substantia nigra

J Neurochem. 2004 Jul;90(1):245-54. doi: 10.1111/j.1471-4159.2004.02496.x.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Dopamine / metabolism
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Male
  • Microdialysis
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Neostriatum / drug effects*
  • Neostriatum / metabolism
  • Nerve Growth Factors / administration & dosage
  • Nerve Growth Factors / pharmacology*
  • Phosphorylation / drug effects
  • Potassium / pharmacology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ret
  • Rats
  • Rats, Inbred F344
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Substantia Nigra / drug effects*
  • Substantia Nigra / metabolism
  • Tyrosine 3-Monooxygenase / metabolism*
  • ras Proteins / metabolism


  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Growth Factors
  • Proto-Oncogene Proteins
  • Amphetamine
  • Tyrosine 3-Monooxygenase
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins
  • Potassium
  • Dopamine