CHOLINERGIC SYSTEMS AND MPTP NEUROTOXICITY

现在有临床和实验证据表明，1-甲基-4- 苯基-1，2，3，6-四氢吡啶（MPTP）诱发帕金森综合征 在人类和猴子身上。 左旋多巴治疗可以逆转 临床症状 对于帕金森病，一种替代方法， 采取补充办法，恢复 胆碱能和多巴胺能对基底神经节的影响， 服用抗胆碱药。 拟议的研究是 部分旨在评估多巴胺能和 MPTP-小鼠模型中的胆碱能神经元系统。 我们 对小鼠模型的观察表明，可能存在一种 正反馈系统加速多巴胺的流失 (DA)如果乙酰胆碱（Ach）活性不受 抗胆碱能药物。 例如，我们发现， 对小鼠施用MPTP，存在DA的下降和 纹状体中乙酰胆碱的升高。 此外， 抗胆碱能药物阻断DA的下降和ACh的上升。 此外，我们有证据表明， MPTP治疗后的阿托品可能使纹状体 恢复其DA含量 我们也有数据表明， 用GM 1神经节苷脂治疗，GM 1是一种内源性物质， 据报道，在突触发生中发挥作用，可能使 纹状体恢复其DA含量。 我们的总体计划 研究内容包括： MPTP对小鼠脑内神经递质的影响 尤其是DA和ACh含量， 合成酶; MPTP诱导的变化的比较 与6-羟基多巴胺引起的变化; MPTP给药后的形态学变化，尤其是 阿托品和GM 1治疗后。 我们理解 运动障碍，已归因于干扰的 基底神经节会明显提前， DA和ACh神经元之间的关系是 更好地理解;事实上，帕金森病的进展 可以通过适当的药物治疗来改变。

There is now clinical and experimental evidence that 1-methyl-4- phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induces parkinsonism in humans and monkeys. Treatment with L-DOPA can reverse the clinical signs. With Parkinson's disease, an alternative and complementary approach to restore the normal balance of cholinergic and dopaminergic influences on basal ganglia is to administer anticholinergic drugs. The proposed studies are designed, in part, to evaluate the interaction of dopaminergic and cholinergic neuronal systems in the MPTP-mouse model. Our observations with the mouse model suggests that there may be a positive feedback system that accelerates the loss of dopamine (DA) if acetylcholine (Ach) activity is not controlled with anticholinergic drugs. For example, we have found that following MPTP administration to the mouse that there is a fall of DA and a rise of ACh in the striatum. Moreover, the administration of anticholinergic drugs block the fall of DA and the rise of ACh. Furthermore, we have evidence that chronic treatment with atropine after treatment with MPTP may enable the striatum to recover its DA content. We also have data suggesting that treatment with GM1 ganglioside, an endogenous substance that has been reported to play a role in synaptogenesis, may enable the striatum to recover its DA content as well. Our general plan of research includes: studies of the characteristics of neurotransmitter change in mouse brain after administering MPTP especially DA and ACh content, their rat of formation and their synthetic enzymes; comparison of the changes induced by MPTP with the changes induced by 6-hydroxydopamine; and studies of the morphological changes after MPTP administration, especially after atropine and GM1 treatment. Our understanding of movement disorders that have been attributed to disturbances of the basal ganglia would be significantly advanced if the relationship between DA- and ACh-containing neurons were understood better; indeed, the progression of Parkinson's disease might be altered with appropriate drug treatment.