Increased extracellular dopamine concentrations and FosB/DeltaFosB expression in striatal brain areas of heterozygous GDNF knockout mice.
Glial cell line-derived neurotrophic factor (GDNF) has been shown to be involved in the maintenance of striatal dopaminergic neurons. To study whether reduced levels of endogenous GDNF affect the striatal dopaminergic transmission we estimated the basal extracellular levels of dopamine in vivo, the basal expression of FosB-related proteins in striatal brain areas as well as the effects of acute and repeated cocaine on locomotor activity and dopamine output in mice lacking one GDNF allele (heterozygous GDNF+/- mice). As expected the striatal GDNF protein content was found to be smaller in the GDNF+/- mice than in their wild-type littermates. Unexpectedly the extracellular dopamine concentration in the GDNF+/- mice in the dorsal striatum (CPu) was 2.0-fold, and in the nucleus accumbens (NAc) 1.6-fold the concentration found in the wild-type littermates. Also FosB/DeltaFosB-like immunoreactivity was found to be elevated in the CPu as well as in the core and in the shell of NAc of the GDNF+/- mice as compared with the wild-type mice. This suggests chronic postsynaptic activation of these brain areas and is in line with elevated extracellular dopamine concentrations. Cocaine's effects acutely and after repeated treatment on locomotor activity were similar in the GDNF+/- and the wild-type mice. Neither did cocaine's acute effects on dopamine output differ between the mice of the two strains. Our findings demonstrate that reduced levels of endogenous GDNF induce alterations in dorsal striatal and accumbal dopaminergic transmission, and stress the importance of endogenous GDNF in the regulation of the dopaminergic neurons.
Airavaara
Mikko
M
Division of Pharmacology and Toxicology, Faculty of Pharmacy, PO Box 56, FIN-00014, University of Helsinki, Finland. mikko.airavaara@helsinki.fi
Planken
Anu
A
Gäddnäs
Helena
H
Piepponen
Timo Petteri
TP
Saarma
Mart
M
Ahtee
Liisa
L
D000344:Afferent Pathways / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
D018491:Dopamine Agonists; C483819:Fosb protein, mouse; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine; D004298:Dopamine