Glial Cell Line-Derived Neurotrophic Factor Increases Stimulus-Evoked Dopamine Release and Motor Speed in Aged Rhesus Monkeys

Abstract

Changes in the functional dynamics of dopamine release and regulation in the basal ganglia have been posited to contribute to age-related slowing of motor functions. Here, we report the effects of glial cell line-derived neurotrophic factor (GDNF) on the stimulus-evoked release of dopamine and motor speed in aged monkeys (21-27 years of age; n = 10). Although no changes were observed in the vehicle controls (n = 5), chronic infusions of 7.5 microg of GDNF per day for 2 months into the right lateral ventricle initially increased hand movement speed up to 40% on an automated hand-reach task. These effects were maintained for at least 2 months after replacing GDNF with vehicle, and increased up to another 10% after the reinstatement of GDNF treatment for 1 month. In addition, upper-limb motor performance times of the aged GDNF-treated animals (n = 5) recorded at the end of the study were similar to those of five young adult monkeys (8-12 years of age). The stimulus-evoked release of dopamine was significantly increased, up to 130% in the right caudate nucleus and putamen and up to 116% in both the right and left substantia nigra of the aged GDNF recipients compared with vehicle controls. Also, basal extracellular levels of dopamine were bilaterally increased, up to 163% in the substantia nigra of the aged GDNF-treated animals. The data suggest that the effects of GDNF on the release of dopamine in the basal ganglia may be responsible for the improvements in motor functions and support the hypothesis that functional changes in dopamine release may contribute to motor dysfunctions characterizing senescence.