Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys

Abstract

Effects of a single injection of either 150 μg human recombinant glial cell line‐derived neurotrophic factor (rGDNF) or vehicle into the right substantia nigra were analyzed in 12 normal adult female rhesus monkeys. The studies included evaluating whole animal behavior, electrochemical recordings of striatal dopamine release, neurochemical determinations of basal ganglia and nigral monoamine levels, and immunohistochemical staining of the nigrostriatal dopamine system. The behavioral effects over the 3–week observation period following trophic factor administration were small, with blinded observers unable to distinguish between GDNF and vehicle‐treated animals. Quantitative measurements did show that five of six trophic factor recipients experienced some weight loss and four of the six GDNF recipients displayed small, but significant, increases in daytime activity levels. In vivo electrochemical recordings in the ipsilateral caudate and putamen 3 weeks after GDNF administration revealed increased potassium‐evoked release of dopamine in trophic factor recipients. In a second series of animals killed at the same time, dopamine levels in the substantia nigra and ventral tegmental area of GDNF recipients were significantly increased, with ipsilateral values more than 200% higher than contralateral and control levels. Levels of the dopamine metabolite HVA were significantly elevated in the substantia nigra, ventral tegmental area, and caudate nucleus ipsilateral to the trophic factor injection. There was a trend toward increased HVA levels in the ipsilateral putamen, nucleus accumbens, and globus pallidus in GDNF‐treated animals, but the ratios of HVA to dopamine were not significantly different between vehicle‐ and GDNF‐treated recipients. Although some tissue damage from the delivery of concentrated trophic factor was evident, dopamine neurons remained in and adjacent to the injection site. In the substantia nigra ipsilateral to GDNF administration, dopamine‐neuron perikaryal size was significantly increased, along with a significant increase in tyrosine hydroxylase‐positive axons and dendrites. We conclude that, in the adult rhesus monkey, a single intranigral GDNF injection induces a significant upregulation of mesencephalic dopamine neurons which lasts for weeks.