Abstract
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 μg GDNF (in 10 μl phosphate-buffered saline) or 10 μl 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+) andd-amphetamine (250 μM)-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.
Footnotes
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Send reprint requests to: Greg A. Gerhardt, Ph.D., Department of Psychiatry, Box C268–71, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262.
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↵1 This work was supported by grants from USPHS NS09199, AG06434 and NIH Training Grant HDO7408–02. In addition, this work was supported, in part, by a Level II Research Scientist Development Award (MH01245) from the National Institutes of Mental Health (to G.G.).
- Abbreviations:
- Amp
- amphetamine
- AP
- anterioposterior
- ANOVA
- analysis of variance
- aCSF
- artificial cerebral spinal fluid
- TC
- clearance rate
- DOPAC
- 3,4-dihydroxyphenylacetic
- DA
- dopamine
- DV
- dorsoventral
- F344
- Fischer 344
- GDNF
- glial cell line-derived neurotrophic factor
- HPLC-EC
- high-performance liquid chromatography coupled with electrochemical detection
- HVA
- homovanillic acid
- 6-OHDA
- 6-hydroxydopamine
- ML
- mediolateral
- PD
- Parkinson’s disease
- PBS
- phosphate-buffered saline
- K+
- potassium
- rhGDNF
- recombinant human glial cell line-derived neurotrophic factor
- 5-HT
- serotonin
- SN
- substantia nigra
- VTA
- ventral tegmental area
- NAc
- nucleus accumbens
- NE
- norepinephrine
- Received December 9, 1996.
- Accepted April 1, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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