Airavaara Mikko, Mijatovic Jelena, Vihavainen Tanja, Piepponen Timo Petteri, Saarma Mart, Ahtee Liisa
Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, FIN-00014, Finland.
Synapse. 2006 May;59(6):321-9. doi: 10.1002/syn.20245.
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.
胶质细胞系源性神经营养因子（GDNF）可调节纹状体多巴胺能神经元。为研究内源性GDNF减少是否会影响吗啡对纹状体多巴胺传递的作用，我们通过体内微透析法估计了缺乏一个GDNF等位基因的小鼠（GDNF+/-小鼠）中多巴胺及其代谢产物的细胞外浓度，并在死后测定了组织浓度。在野生型小鼠中，急性注射吗啡（5和10mg/kg，皮下注射）可使伏隔核多巴胺输出量呈剂量依赖性增加（分别最大增加30%和80%）。在GDNF+/-小鼠中，5mg/kg吗啡可使伏隔核多巴胺输出量最大增加110%，且显著高于10mg/kg吗啡（最大增加60%）。此外，GDNF+/-小鼠中细胞外伏隔核3,4-二羟基苯乙酸（DOPAC）对急性吗啡的反应也有显著改变。在两种基因型的小鼠中，尾壳核中对吗啡的反应与伏隔核中的相似，但强度要小得多。5、10和30mg/kg剂量的吗啡可使纹状体组织中DOPAC和高香草酸（HVA）的浓度呈剂量依赖性升高，但30mg/kg剂量的吗啡在GDNF+/-小鼠中的作用明显小于其野生型同窝小鼠。[(3)H]DAMGO与纹状体膜匀浆的结合在两种基因型之间相似。然而，吗啡在GDNF+/-小鼠中诱导镇痛所需的剂量比对照组小。GDNF水平降低会改变吗啡对纹状体多巴胺的作用这一发现，以及我们之前在GDNF+/-小鼠中发现的细胞外纹状体多巴胺浓度升高和FosB/DeltaFosB表达增加，都表明GDNF在调节纹状体多巴胺能系统中具有重要作用。
