GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys

Greg A. Gerhardt, Wayne A. Cass, Peter Huettl, Scot Brock, Zhiming Zhang, Don M. Gash

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88 Scopus citations

Abstract

Microdialysis measurements of dopamine (DA) and DA metabolites were carried out in the putamen and substantia nigra of unilateral l-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys that received intraventricular injections of vehicle or glial-derived neurotrophic factor (GDNF, 300 μg) 3 weeks prior to the microdialysis studies. Following behavioral measures in the MPTP-lesioned monkeys, they were anesthetized with isoflurane and placed in a stereotaxic apparatus. Magnetic resonance imaging (MRI)-guided sterile stereotaxic procedures were used for implantations of the microdialysis probes. Basal extracellular levels of DA and the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were found to he decreased by > 95% in the right putamen of the MPTP- lesioned monkeys as compared to normal animals. In contrast, basal DA levels were not significantly decreased, and DOPAC and HVA levels were decreased by only 65% and 30%, respectively, in the MPTP-lesioned substantia nigra. Significant reductions in D-amphetamine-evoked DA release were also observed in the MPTP-lesioned substantia nigra and putamen of the monkeys as compared to normal animals. A single intraventricular administration of GDNF into one group of MPTP-lesioned monkeys elicited improvements in the parkinsonian symptoms in these animals at 2-3 weeks post-administration. In addition, v- amphetamine-evoked overflow of DA was significantly increased in the substantia nigra but not the putamen of MPTP-lesioned monkeys that had received GDNF. Moreover, post-mortem brain tissue studies showed increases in whole tissue levels of DA and DA metabolite levels primarily within the substantia nigra in MPTP-lesioned monkeys that had received GDNF. Taken together, these data support that single ventricular infusions of GDNF produce improvements in motoric behavior in MPTP-lesioned monkeys that correlate with increases in DA neuronal function that are localized to the substantia nigra and not the putamen.

Original languageEnglish
Pages (from-to)163-171
Number of pages9
JournalBrain Research
Volume817
Issue number1-2
DOIs
StatePublished - Jan 30 1999

Bibliographical note

Funding Information:
This work was supported by grants from USPHS NS-25778 and AG13494 to Don Gash, and NS-09199, AG-06434, AG13494 and a Level II Research Scientist Development Award (MH-01245) to Greg Gerhardt. We would like to express our thanks to Dr. Malcolm Avison from the University of Kentucky for his help with the MRI scans that were performed on the monkeys. In addition, we would like to thank Dr. Paul Lapchak for helpful discussions. Finally, this work would not have been possible without the RhGDNF that was supplied by Amgen.

Keywords

  • Dopamine
  • Microdialysis
  • Monkey
  • Parkinson's disease
  • Substantia nigra

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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