In heterozygous GDNF knockout mice the response of striatal dopaminergic system to acute morphine is altered.
Glial cell line-derived neurotrophic factor (GDNF) regulates striatal dopaminergic neurons. To study whether reduced endogenous GDNF affect morphine's effects on striatal dopamine transmission, we estimated extracellular concentrations of dopamine and its metabolites by microdialysis in vivo and tissue concentrations post mortem in mice lacking one GDNF allele (GDNF+/- mice). In the wild-type mice, acute morphine (5 and 10 mg/kg s.c.) increased accumbal dopamine output dose-dependently (maximally by 30 and 80%, respectively). In the GDNF+/- mice, 5 mg/kg of morphine enhanced the accumbal dopamine output maximally by 110%, and significantly more than morphine 10 mg/kg (maximally by 60%). Also, the response of extracellular accumbal DOPAC to acute morphine was significantly altered in the GDNF+/- mice. In mice of both genotypes, the responses to morphine in the caudate putamen were similar to but much less intense than those in the nucleus accumbens. Morphine at the doses 5, 10, and 30 mg/kg dose-dependently elevated the striatal tissue concentrations of DOPAC and HVA, but the effect of 30 mg/kg was significantly smaller in the GDNF+/- mice than in their wild-type littermates. The binding of [(3)H]DAMGO to striatal membrane homogenates was similar between the genotypes. However, morphine induced antinociception in the GDNF+/- mice at a smaller dose than in the controls. The finding that reduced GDNF level alters the effects of morphine on striatal dopamine and our previous findings of elevated extracellular striatal dopamine concentrations and FosB/DeltaFosB expression in the GDNF+/- mice show the importance of GDNF in the regulation of striatal dopaminergic system.
Airavaara
Mikko
M
Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, FIN-00014, Finland. mikko.airavaara@helsinki.fi
Mijatovic
Jelena
J
Vihavainen
Tanja
T
Piepponen
Timo Petteri
TP
Saarma
Mart
M
Ahtee
Liisa
L
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000493:pharmacokinetics; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000172:deficiency* / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011930:Reaction Time / Q000187:drug effects; D018709:Statistics, Nonparametric; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D000701:Analgesics, Opioid; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009294:Narcotics; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D015102:3,4-Dihydroxyphenylacetic Acid; D009020:Morphine; D004298:Dopamine; D006719:Homovanillic Acid