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The purpose of this study was to examine whether improvement in motor function could be demonstrated in old rats, and to see if GDNF affected post-synaptic DA function. Aged (20 month old) versus young rats were tested following GDNF treatment for postural control by using an inclined balance beam and a wire grip strength test. Rats were also examined electrophysiologically for spontaneous striatal cell firing rate alone and in the presence of DA receptor agonists, and histologically for the intensity of striatal TH staining, and number of DA containing nigral cells. Behavior was significantly improved in the aged animals who received central GDNF infusions, although the extent of improvement was less than what has been observed in 16-month-old rats. There was no effect of GDNF treatment in the aged animals on spontaneous firing rate in the striatum, or on the post synaptic response to locally applied D(1) and D(2) receptor family agonists. However, there was an effect of age alone on firing rate, and on the response to locally applied SKF 38393 and quinpirole. By using unbiased cell counting we observed no age-related decline in the number of TH positive cells in the substantia nigra. There was no effect of GDNF on the number of TH positive cells in the substantia nigra in either young or aged rats, although there were morphological improvements in DA neurons of the GDNF treated aged rats. These results replicate earlier studies showing an effect of age on striatal firing rate and dopamine receptor function, and suggest that the GDNF mediated improvement in behavior may be located other than post synaptically within the striatum.

In order to evaluate the efficacy of glial cell line-derived neurotrophic factor (GDNF) in a model of advanced Parkinson's disease, we studied rats with extensive bilateral lesions of the nigrostriatal pathway. Adult male F344 rats were injected bilaterally into the medial forebrain bundle with the neurotoxin 6-hydroxydopamine. Locomotor ability as measured by total distance traveled in an open field over 20 min, as well as von Frey hair testing of sensorimotor neglect, was monitored weekly. Rats demonstrating severe motor impairment and sensorimotor neglect were used for this study and were sorted to achieve similar average behavioral scores between the two treatment groups. After 2 weeks of pretesting, the rats received 250 microg GDNF or vehicle injected into the right lateral cerebral ventricle. Three weeks later, an additional 500 microg GDNF or vehicle was injected into the contralateral ventricle. The rats were monitored for another 2 weeks prior to sacrifice. Behavioral results indicated that von Frey hair scores were inconsistent between tests for each rat and were unchanged following GDNF treatment. However, GDNF recipients demonstrated significant improvement in locomotor ability compared to vehicle recipients. High-pressure liquid chromatography-electrochemical detection analysis of neurotransmitter levels revealed a significant increase in dopamine content within the substantia nigra and ventral tegmenta, but not the striata, of GDNF-treated rats. Further, immunohistochemical staining of tissues from matched pairs of rats revealed increased numbers of tyrosine hydroxylase-positive ventral mesencephalic neurons in one of the two pairs of rats examined. These results suggest that intracerebroventricular GDNF administration improves motor ability and supports nigrostriatal dopaminergic neurons in a model of severe Parkinson's disease.

Aging is accompanied with declines in motoric function which may be the result of deficits in central nervous system dopaminergic function. Glial cell line-derived neurotrophic factor (GDNF) has been shown to have neuroprotective and restorative effects on dopaminergic neurons of the nigrostriatal pathway in young rats. In this study, 10, 40, or 60 micrograms GDNF or vehicle was injected intrastriatally in 16-17 month old Fischer 344 rats. Coordination and muscle strength as determined by performance on an inclined balance beam and a wire grip strength test were monitored for up to 5 weeks post-injection. GDNF elicited dose-dependent improvements in motor coordination without concurrent increases in strength. The highest dose tested produced > 79% improvement in motor coordination, resulting in performance scores approaching those achieved by 3 month old rats tested concurrently. These findings indicate GDNF produces profound improvement in the motoric function of mature rats, which may be related to dopaminergic circuits.

Glial cell-lined derived neurotrophic factor (GDNF) has been shown to promote survival of developing mesencephalic dopaminergic neurons in vitro. In order to determine if there is a positive effect of GDNF on injured adult midbrain dopaminergic neurons in situ, we have carried out experiments in which a single dose of GDNF was injected into the substantia nigra following a unilateral lesion of the nigrostriatal system. Rats were unilaterally lesioned by a single stereotaxic injection of 6-hydroxydopamine (6-OHDA; 9 micrograms/4 microliters normal saline with 0.02% ascorbate) into the medial forebrain bundle and tested weekly for apomorphine-induced (0.05 mg/kg s.c.) contralateral rotation behavior. Rats that manifested > 300 turns/hour received a nigral injection of 100 micrograms GDNF, or cytochrome C as a control, 4 weeks following the 6-OHDA lesion. Rotation behavior was quantified weekly for 5 weeks after GDNF. Rats were subsequently anesthetized, transcardially perfused, and processed for tyrosine hydroxylase immunohistochemistry. It was found that 100 micrograms GDNF decreased apomorphine-induced rotational behavior by more than 85%. Immunohistochemical studies revealed that tyrosine hydroxylase immunoreactivity was equally reduced in the striatum ipsilateral to the lesion in both cytochrome C and GDNF-injected animals. In contrast, large increments in tyrosine hydroxylase immunoreactivity were observed in the substantia nigra of animals treated with 100 micrograms of GDNF, with a significant increase in numbers of tyrosine hydroxylase-immunoreactive cell bodies and neurites as well as a small increase in the cell body area of these neurons. The results suggest that GDNF can maintain the dopaminergic neuronal phenotype in a number of nigral neurons following a unilateral nigrostriatal lesion in the rat.