Glial cell line-derived neurotrophic factor: the lateral cerebral ventricle as a site of administration for stimulation of the substantia nigra dopamine system in rats.
The direct application of recombinant human glial cell line-derived neurotrophic factor (rhGDNF) to the deep structures of the nigrostriatum has been shown previously to augment dopamine function and inhibit loss of substantia nigra neurons in rodent models of Parkinson's disease. The present studies were designed to determine whether administration of rhGDNF into the lateral ventricle, a more clinically accessible intracranial target, is capable of augmenting dopamine function of the nigrostriatal pathway in normal rats. Single bolus intracerebroventricular (i.c.v) injections of rhGDNF increased locomotor activity and decreased food and water consumption and body weight gain in a dose-dependent manner. rhGDNF increased concentrations of dopamine and dopamine metabolites in the substantia nigra, ventral tegmental area and hypothalamus, but had no significant effects in the striatum. rhGDNF had no effect on striatal or substantia nigral serotonin (5-HT) and 5-hydroxyindoleacetic acid levels, but these levels were significantly increased in the ventral tegmental area and hypothalamus respectively. The augmentation of the dopamine and 5-HT systems was detected 2 weeks but not 3 days or 6 weeks after rhGDNF administration. After a repeat injection of i.c.v rhGDNF (6 weeks after the initial injection), substantia nigral dopamine, 5-HIAA and noradrenalin levels were increased. These results indicate that i.c. v administration of rhGDNF has an influence on adult rat dopamine neurons. This route of administration may be useful for stimulating dopamine neurons in Parkinson's disease.
Martin
D
D
Department of Inflammation, Amgen Boulder Inc., 3200 Walnut Street, Boulder, CO 80301, USA.
Miller
G
G
Fischer
N
N
Diz
D
D
Cullen
T
T
Russell
D
D
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects; D007276:Injections, Intraventricular; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000494:pharmacology; D013268:Stimulation, Chemical; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects
D015306:Biogenic Monoamines; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D004298:Dopamine