Intranigral or intrastriatal injections of GDNF: effects on monoamine levels and behavior in rats.
The present studies were designed to determine whether administration of recombinant human glial cell line-derived neurotrophic factor (rhGDNF) into either the substantia nigra or striatum is capable of augmenting dopamine function of the nigrostriatal pathway in normal rats. Single bolus intracranial injections of rhGDNF at either site increased locomotor activity and decreased food and water consumption and body weight in a dose-dependent manner when compared to vehicle-treated animals. These behavioral responses returned to pre-control levels within 3 weeks post rhGDNF administration. Administration of rhGDNF intranigrally increased dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels of the ipsilateral substantia nigra at 2 and 6 weeks post injection but had no augmenting effects on dopamine or its metabolites in the striatum. Administration of rhGDNF intrastriatally increased DOPAC and HVA levels of the ipsilateral striatum, although striatal dopamine levels were unchanged. Ipsilateral nigral dopamine levels were increased after intrastriatal injection of rhGDNF. The effects of intracranial rhGDNF were not specific to the nigrostriatal dopamine system, since nigrostriatal serotonin, 5-hydroxyindoleacetic acid (5-HIAA), epinephrine and norepinephrine transmitter levels were altered depending on administration route for rhGDNF and dose. Taken together, these data demonstrate long-lasting neurochemical and behavioral changes which suggest that rhGDNF can augment function in adult rat dopamine neurons. Therefore, rhGDNF may have therapeutic potential for Parkinson's disease.
Martin
D
D
Department of Inflammation, Amgen Inc., Boulder, CO 80301, USA.
Miller
G
G
Cullen
T
T
Fischer
N
N
Dix
D
D
Russell
D
D
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007267:Injections; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
D015306:Biogenic Monoamines; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011994:Recombinant Proteins