In heterozygous GDNF knockout mice the response of striatal dopaminergic system to acute morphine is altered
In heterozygous GDNF knockout mice the response of striatal dopaminergic system to acute morphine is altered
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DOI：
10.1002/syn.20245
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发表时间：
2006-05-01
期刊：
影响因子：
2.3
通讯作者：
Ahtee, L
中科院分区：
文献类型：
--
作者：
Airavaara, M;Mijatovic, J;Ahtee, L
神经胶质细胞系来源的神经营养因子（GDNF）调控纹状体多巴胺能神经元。为了研究内源性GDNF减少是否会影响吗啡对纹状体多巴胺传递的影响，我们通过体内微透析和缺乏GDNF一个等位基因的小鼠（GDNF+/-小鼠）死后的组织浓度估算了多巴胺及其代谢物的细胞外浓度。在野生型小鼠中，急性吗啡（5和10 mg/kg s.c）剂量依赖性地增加伏隔多巴胺输出（最大分别增加30%和80%）。在GDNF+/-小鼠中，5 mg/kg吗啡使伏隔多巴胺输出最大增加11.0%，显著高于10 mg/kg吗啡（最大增加60%）。此外，在GDNF+/-小鼠中，细胞外伏隔DOPAC对急性吗啡的反应显著改变。在两种基因型的小鼠中，尾状壳核对吗啡的反应与伏隔核相似，但强度要小得多。吗啡剂量为5、10和30 mg/kg时，纹状体组织中DOPAC和HVA浓度呈剂量依赖性升高，但30 mg/kg对GDNF+/-小鼠的影响明显小于野生型小鼠。[H-3]DAMGO与纹状膜匀浆的结合在不同基因型之间相似。然而，吗啡在GDNF+/-小鼠中诱导的抗痛觉作用比对照组小。GDNF水平的降低改变了吗啡对纹状体多巴胺的影响，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和FosB/Delta FosB表达升高，这表明GDNF在纹状体多巴胺能系统的调节中具有重要作用。
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 11.0%, 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 [H-3]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/Delta FosB expression in the GDNF+/- mice show the importance of GDNF in the regulation of striatal dopaminergic system.