Behavioral and neurochemical effects of intranigral administration of glial cell line-derived neurotrophic factor on aged Fischer 344 rats.

To investigate the efficacy of glial cell line-derived neurotrophic factor (GDNF) in the augmentation of functional dopaminergic (DAergic) indices in aged rats, 24-month-old Fischer 344 (F344) rats received single intranigral injections of 10 microg GDNF (in 10 microl phosphate-buffered saline) or 10 microl phosphate-buffered saline. In locomotor activity tests, the GDNF-treated animals exhibited significant increases in both total distance traveled and movement speed compared with the vehicle group, 3 weeks after injections. In vivo microdialysis studies showed that basal extracellular levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were significantly increased in the striatum of the GDNF-treated rats. In addition, both potassium- (100 mM, K+) and d-amphetamine (250 microM)-induced DA overflow were augmented in the striatum and nucleus accumbens of the aged rats injected with GDNF. Whole-tissue levels of DA and DA metabolites, as measured by high-performance liquid chromatography coupled with electrochemical detection, in the nucleus accumbens and substantia nigra were also elevated after GDNF administration. These results indicate that a single intranigral injection of GDNF is capable of augmenting locomotor behavior and DAergic function in the aged rat striatum and nucleus accumbens. This is the first report to demonstrate that a single intranigral injection of GDNF can improve the functional capacity of DAergic neurons of aged F344 rats.