Increased extracellular dopamine concentrations and FosB/ΔFosB expression in striatal brain areas of heterozygous GDNF knockout mice
Increased extracellular dopamine concentrations and FosB/ΔFosB expression in striatal brain areas of heterozygous GDNF knockout mice
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DOI：
10.1111/j.1460-9568.2004.03700.x
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发表时间：
2004-11-01
影响因子：
3.4
通讯作者：
Ahtee, L
中科院分区：
文献类型：
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作者：
Airavaara, M;Planken, A;Ahtee, L
胶质细胞源性神经营养因子（GDNF）已被证明参与纹状体多巴胺能神经元的维持。为了研究内源性GDNF水平的降低是否影响纹状体多巴胺能传递，我们估计了体内多巴胺的基础细胞外水平，纹状体脑区FosB相关蛋白的基础表达以及急性和重复可卡因对缺乏一个GDNF等位基因的小鼠（杂合GDNF+/-小鼠）的运动活性和多巴胺输出的影响。正如预期的那样，发现GDNF+/-小鼠中的纹状体GDNF蛋白含量比其野生型同窝仔中的小。出乎意料的是，GDNF+/-小鼠的背侧纹状体（CPu）中的细胞外多巴胺浓度是野生型同窝仔中发现的浓度的2.0倍，而在中脑核（NAc）中是野生型同窝仔中发现的浓度的1.6倍。与野生型小鼠相比，GDNF+/-小鼠的CPu以及NAc的核心和外壳中的FosB/DeltaFosB样免疫反应性也被发现升高。这表明这些脑区的慢性突触后激活，并与细胞外多巴胺浓度升高一致。在GDNF+/-小鼠和野生型小鼠中，皮质醇对自发活动的急性和重复治疗后的作用相似。可卡因对多巴胺分泌的急性影响在两种品系的小鼠之间也没有差异。我们的研究结果表明，内源性GDNF水平的降低诱导背侧纹状体和延髓多巴胺能传递的改变，并强调内源性GDNF在多巴胺能神经元的调节中的重要性。
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.