MORPHOLOGICAL AND FUNCTIONAL-EFFECTS OF INTRANIGRALLY ADMINISTERED GDNF IN NORMAL RHESUS-MONKEYS

Effects of a single injection of either 150 mu g human recombinant gli al cell line-derived neurotrophic factor (rGDNF) or vehicle into the r ight substantia nigra were analyzed in 12 normal adult female rhesus m onkeys. The studies included evaluating whole animal behavior, electro chemical recordings of striatal dopamine release, neurochemical determ inations of basal ganglia and nigral monoamine levels, and immunohisto chemical staining of the nigrostriatal dopamine system. The behavioral effects over the 3-week observation period following trophic factor a dministration were small, with blinded observers unable to distinguish between CDNF- and vehicle-treated animals. Quantitative measurements did show that five of six trophic factor recipients experienced some w eight loss and four of the six GDNF recipients displayed small, but si gnificant, increases in daytime activity levels. In vivo electrochemic al recordings in the ipsilateral caudate and putamen 3 weeks after GDN F administration revealed increased potassium-evoked release of dopami ne 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 i psilateral values more than 200% higher than contralateral and control levels. Levels of the dopamine metabolite HVA were significantly elev ated in the substantia nigra, ventral tegmental area, and caudate nucl eus ipsilateral to the trophic factor injection. There was a trend tow ard increased HVA levels in the ipsilateral putamen, nucleus accumbens , and globus pallidus in GDNF-treated animals, but the ratios of HVA t o dopamine were not significantly different between vehicle- and GDNF- treated recipients. Although some tissue damage from the delivery of c oncentrated trophic factor was evident, dopamine neurons remained in a nd adjacent to the injection site. In the substantia nigra ipsilateral to GDNF administration, dopamine-neuron perikaryal size was significa ntly increased, along with a significant increase in tyrosine hydroxyl ase-positive axons and dendrites. We conclude that, in the adult rhesu s monkey, a single intranigral GDNF injection induces a significant up regulation of mesencephalic dopamine neurons which lasts for weeks. (C ) 1995 Wiley-Liss, Inc.