Dysregulation of striatal dopamine release in a mouse model of dystonia
Dysregulation of striatal dopamine release in a mouse model of dystonia
复制标题
DOI：
10.1111/j.1471-4159.2010.06890.x
复制
发表时间：
2010-09-01
影响因子：
4.7
通讯作者：
Rice, Margaret E.
中科院分区：
文献类型：
--
作者：
Bao, Li;Patel, Jyoti C.;Rice, Margaret E.
肌张力障碍是一种以不自主运动为特征的神经系统疾病。我们研究了纹状体多巴胺（DA）的功能，在过度活跃的转基因（Tg）小鼠产生的肌张力障碍模型。诱发的细胞外DA浓度进行监测与碳纤维微电极和快速扫描循环伏安法在纹状体切片从非Tg小鼠，Tg小鼠具有阳性运动表型，和表型阴性Tg同窝仔。峰值单脉冲诱发的细胞外DA浓度显着低于表型阳性小鼠比非Tg或表型阴性小鼠，但非Tg和表型阴性小鼠之间无法区分。表型阳性小鼠也有更高的功能性D2 DA自身受体的敏感性比非Tg小鼠，这将与较低的细胞外DA浓度在体内一致。多脉冲（相位）刺激（5个脉冲，10-100 Hz）显示增强的频率依赖性诱发DA释放的表型阳性与非Tg或表型阴性小鼠，这是加剧时，细胞外Ca 2+浓度降低。表型阳性小鼠对阶段性刺激的敏感性增强，这让人联想到烟碱乙酰胆碱受体拮抗作用的模式。与改变胆碱能调节的作用一致，当烟碱受体被美加明阻断时，组间阶段性反应的差异消失。总之，这些数据暗示受损的DA释放调节，可能来自胆碱能功能障碍，在这种肌张力障碍模型的运动症状。
Dystonia is a neurological disorder characterized by involuntary movements. We examined striatal dopamine (DA) function in hyperactive transgenic (Tg) mice generated as a model of dystonia. Evoked extracellular DA concentration was monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry in striatal slices from non-Tg mice, Tg mice with a positive motor phenotype, and phenotype-negative Tg litter-mates. Peak single-pulse evoked extracellular DA concentration was significantly lower in phenotype-positive mice than in non-Tg or phenotype-negative mice, but indistinguishable between non-Tg and phenotype-negative mice. Phenotype-positive mice also had higher functional D2 DA autoreceptor sensitivity than non-Tg mice, which would be consistent with lower extracellular DA concentration in vivo. Multiple-pulse (phasic) stimulation (five pulses, 10-100 Hz) revealed an enhanced frequency dependence of evoked DA release in phenotype-positive versus non-Tg or phenotype-negative mice, which was exacerbated when extracellular Ca2+ concentration was lowered. Enhanced sensitivity to phasic stimulation in phenotype-positive mice was reminiscent of the pattern seen with antagonism of nicotinic acetylcholine receptors. Consistent with a role for altered cholinergic regulation, the difference in phasic responsiveness among groups was lost when nicotinic receptors were blocked by mecamylamine. Together, these data implicate compromised DA release regulation, possibly from cholinergic dysfunction, in the motor symptoms of this dystonia model.