Dopaminergic modulation of early signs of excitotoxicity in visualized rat neostriatal neurons
Dopaminergic modulation of early signs of excitotoxicity in visualized rat neostriatal neurons
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DOI：
10.1046/j.1460-9568.1998.00357.x
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发表时间：
1998-11-01
影响因子：
3.4
通讯作者：
Levine, MS
中科院分区：
文献类型：
--
作者：
Cepeda, C;Colwell, CS;Levine, MS
由兴奋性氨基酸受体激活引起的细胞肿胀可能是最终导致细胞死亡的毒性级联反应的第一步。之前我们表明，水浴应用N-甲基-D-天冬氨酸（NMDA）或红藻氨酸（KA）会导致新纹状体细胞肿胀。本实验研究了多巴胺（DA）及其受体激动剂对NMDA和KA诱导的细胞肿胀的调节作用。利用Nomarski光学和红外视频显微镜在大鼠幼仔（出生后12-18天）的厚切片中观察新纹状体中等大小的神经元，体细胞横截面积的增加作为谷氨酸受体激动剂浴应用诱导的肿胀的指标。NMDA以剂量依赖性方式诱导细胞肿胀。在没有NMDA的情况下，DA受体的激活不产生肿胀。DA和D-1受体激动剂SKF 38393，增加由NMDA产生的肿胀的幅度。在存在D-1受体拮抗剂SCH 23390的情况下，该作用降低。与此相反，D-2受体的激活quinpirole减少NMDA诱导的细胞肿胀的幅度。DA轻微减弱KA受体激活引起的细胞肿胀。Quinpirole产生了显着的浓度依赖性减少KA诱导的肿胀，而SKF 38393增加KA诱导的肿胀，但仅在低浓度的KA。总之，这些结果提供了额外的支持的假设，即DA调制的方向取决于谷氨酸受体亚型，以及DA受体亚型激活。这些观察结果的一个可能的结果是，内源性DA可能是亨廷顿病细胞死亡机制中的一个重要因素。
Cell swelling induced by activation of excitatory amino acid receptors is presumably the first step in a toxic cascade that may ultimately lead to cell death. Previously we showed that bath application of N-methyl-D-aspartate (NMDA) or kainate (KA) produces swelling of neostriatal cells. The present experiments examined modulation of NMDA and KA-induced cell swelling by dopamine (DA) and its receptor agonists. Nomarski optics and infra-red videomicroscopy were utilized to visualize neostriatal medium-sized neurons in thick slices from rat pups (12-18 postnatal days), increase in somatic cross-sectional area served as the indicator of swelling induced by bath application of glutamate receptor agonists. NMDA induced cell swelling in a dose-dependent manner. Activation of DA receptors in the absence of NMDA did not produce swelling. DA and the D-1 receptor agonist SKF 38393, increased the magnitude of swelling produced by NMDA. This effect was reduced in the presence of the D-1 receptor antagonist, SCH 23390. In contrast, activation of D-2 receptors by quinpirole decreased the magnitude of NMDA-induced cell swelling. DA slightly attenuated cell swelling induced by activation of KA receptors. Quinpirole produced a significant concentration-dependent reduction in KA-induced swelling while SKF38393 increased KA-induced swelling, but only at a low concentration of KA. Together, these results provide additional support for the hypothesis that the direction of DA modulation depends on the glutamate receptor subtype, as well as the DA receptor subtype activated. One possible consequence of these observations is that endogenous DA may be an important contributing factor in the mechanisms of cell death in Huntington's disease.