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。L多巴治疗可逆转 临床症状。帕金森氏症，另一种选择 辅助性方法以恢复正常的平衡 胆碱能和多巴胺能对基底节的影响 使用抗胆碱能药物。建议进行的研究包括 设计部分是为了评估多巴胺能和 MPTP-小鼠模型中的胆碱能神经元系统。我们的 对老鼠模型的观察表明，可能存在一个 加速多巴胺损失的正反馈系统 (DA)如果乙酰胆碱(Ach)活性不受控制 抗胆碱能药物。例如，我们发现以下内容 MPTP给鼠标用药，说明有一个DA和一个 纹状体内ACh升高。此外，行政管理， 抗胆碱能药物可阻断DA的下降和ACh的升高。 此外，我们有证据表明，慢性药物治疗 经MPTP治疗后的阿托品可使纹状体 恢复其DA含量。我们也有数据表明 GM1神经节苷脂治疗，一种内源性物质， 已被报道在突触发生中发挥作用，可能使 纹状体也可恢复其DA含量。我们的总体规划是 研究内容包括：研究 MPTP对小鼠脑内神经递质的影响 尤其是DA和ACh的含量，它们的形成速度和它们的 合成酶.MPTP引起的变化的比较 与6-羟基多巴胺引起的变化；以及对 MPTP给药后的形态变化，尤其是 阿托品和GM1治疗后。我们对此的理解 运动障碍被归因于运动障碍 基底节将显著提前，如果 多巴胺能神经元与ACh能神经元的关系是 更好地理解；事实上，帕金森氏症的进展 可能会通过适当的药物治疗而改变。

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.