DOPAMINE-INDUCED NEUROTOXICITY IN A CATECHOLAMINERGIC CELL LINE

大脑中过度活跃的多巴胺能神经元被认为是 在精神分裂症的病因学中起重要作用。 已经假设 长时间暴露于过量的 多巴胺或多巴胺的氧化代谢产物可以产生神经元 损伤，细胞死亡，并部分负责一些负面的 精神分裂症的症状 儿茶酚胺已被证明具有神经毒性 去甲肾上腺素和多巴胺神经元（J Neurosci Res 26：428，1990; J Pharmacol Exp Ther 262：1274，1992）。 我们正在评估 多巴胺的神经毒性作用，通过使用克隆细胞系开发， Chikaraishi和同事（J Neurosci 13：1280，1993）。 该细胞系 来源于从CNS获得的酪氨酸羟化酶阳性肿瘤， 转基因小鼠携带SV 40 T抗原癌基因， 大鼠酪氨酸羟化酶基因的转录控制。 我们发现 将CATH. a细胞与多巴胺一起孵育， 最高浓度的多巴胺（500 μ M）杀死65%的 相对于未处理的细胞。 我们评估了 多巴胺的毒性是受体介导的现象， 多种D1和D2激动剂和拮抗剂。 Quinpirole，选择性D2 激动剂没有神经毒性，而用D1. 激动剂（6-溴阿帕，SKF 38393）产生剂量依赖性细胞死亡， 其中84%的细胞在100 μ M的浓度下死亡。 孵育 用10 μ M选择性D1拮抗剂（SCH 23390，SKF 83566）不产生细胞死亡。 细胞的伴随处理是 D1激动剂（100 μ M）和D1拮抗剂（100 μ M）部分阻止了 D1激动剂的神经毒性。 这些数据支持这样的假设， 多巴胺对儿茶酚胺能神经元具有神经毒性， 神经毒性部分由D1受体介导。

Overactive dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. It has been hypothesized that prolonged exposure of catecholamine neurons to excessive levels of dopamine or to the oxidative metabolites of dopamine may produce neuronal damage, cell death, and be partially responsible for some of the negative symptoms of schizophrenia. Catecholamines have been shown to be neurotoxic to norepinephrine and dopamine neurons in primary culture (J Neurosci Res 26:428, 1990; J Pharmacol Exp Ther 262:1274, 1992). We are evaluating the neurotoxic effects of dopamine by using a clonal cell line developed by Chikaraishi and co-workers (J Neurosci 13:1280, 1993). This cell line was derived from a tyrosine hydroxylase positive tumor obtained from the CNS of transgenic mice carrying the SV 40 T antigen oncogene under the transcriptional control of the rat tyrosine hydroxylase gene. We found that incubation of CATH.a cells with dopamine produced dose-dependent cell death, with the highest concentration of dopamine (500 muM) killing 65% of the cells relative to untreated cells. We evaluated the possibility that the toxicity of dopamine is a receptor-mediated phenomenon by using a variety of D1 and D2 agonists and antagonists. Quinpirole, a selective D2 agonist was not neurotoxic, whereas incubation of CATH.a cells with D1 agonists (6-Bromo APA, SKF 38393) produced a dose-dependent cell death, with 84% of the cells dying at a concentration of 100 muM. Incubation of the cells with 10 muM of the selective D1 antagonists (SCH 23390, SKF 83566) produced no cell death. The concomitant treatment of the cells with D1 agonists (100 muM) and D1 antagonists (100 muM) partially prevented the neurotoxicity of the D1 agonists. These data support the hypothesis that dopamine is neurotoxic to catecholaminergic neurons and that this neurotoxicity is partially mediated by D1 receptors.