NEUROCHEMISTRY OF THERAPEUTICS IN PARKINSON'S DISEASE

拟议研究的长期目标是了解， 在生物化学水平上， L-DOPA作为治疗剂用于改善 帕金森病的症状 此外，我们希望确定 这些潜在的机制， 帕金森病患者耐受左旋多巴的能力下降 由于不必要的副作用，通常出现在5至8 多年来服用药物。 尽管它作为一种治疗药物有缺点， L-DOPA仍然是最有效和广泛使用的药物， 一种治疗帕金森病的化合物。通过更好 了解与有益的， 以及L-DOPA的不良行为，我们将增加我们的 这种疾病的知识，然后可以适用于 开发改进的治疗策略。 且此种 这些信息将有助于我们了解正常的 以及基底神经节功能紊乱 拟议 研究将利用6-OHDA处理的大鼠作为动物模型， 帕金森氏症。 体内微透析，一种能够 反复测量细胞外神经递质水平， 在清醒动物中进行，将用于确定 纹状体多巴胺释放的特征 左旋多巴对帕金森病早期动物模型的影响 当黑质纹状体多巴胺的损失只是部分的疾病。 这些数据将与以前的结果进行比较， 动物模型的最后阶段的障碍时，黑质纹状体 多巴胺退化几乎完全 我们亦建议 探索药物操作的可能性， 纹状体5-羟色胺神经支配，这是相对幸免于晚 帕金森综合征阶段，可能提供一种方法， 生理来源的多巴胺形成的左旋多巴， 严重缺乏多巴胺的动物，这种方法 可能最终证明是有用的， 突发的不必要的副作用 最后，我们建议评估 作用于基底神经节部位的多巴胺的贡献 纹状体中的主要靶区对生化效应的影响 在这个动物模型中发生的左旋多巴， 这种化合物在基底神经节中的作用 整个电路。

The long-term objective of the proposed research is to understand, at the biochemical level, the basis for the remarkable initial efficacy of L-DOPA as a therapeutic agent for ameliorating the symptoms of Parkinson's disease. Further, we wish to determine the underlying mechanisms that are responsible for the eventual decline in the ability of Parkinsonian patients to tolerate L-DOPA due to unwanted side effects that emerge usually after five to eight years of taking the drug. Despite its shortcomings as a therapeutic agent, L-DOPA remains the most efficacious and widely utilized compound for treating Parkinsonian symptomatology. By better understanding the neurobiology associated with the beneficial as well as the undesirable actions of L-DOPA we will increase our knowledge of this disorder which then ca be applied to the development of improved therapeutic strategies. In addition, such information will contribute to our understanding of both normal and disordered functioning of the basal ganglia. The proposed studies will utilize the 6-OHDA treated rat as an animal model of Parkinson's disease. In vivo microdialysis, a method enabling repeated measurements of extracellular neurotransmitter levels to be conducted in awake animals, will be employed to determine the characteristics of striatal dopamine release after administration of L-DOPA to animals modelling the early stage of Parkinson's disease when the loss of nigrostriatal dopamine is only partial. These data will be compared to previous results obtained in animals modelling the final stage of the disorder when nigrostriatal dopamine degeneration is nearly complete. We also propose to explore the possibility that pharmacological manipulation of the striatal serotonin innervation, which is relatively spared in the late stage of Parkinsonism, may provide means to supply a physiological source of dopamine formed from L-DOPA in severely dopamine-depleted animals and that such an approach may ultimately prove useful for circumventing the problem of emergent, unwanted side effects. Finally, we propose to evaluate the contribution of dopamine acting at basal ganglia sites outside of the primary target region in striatum to the biochemical effects of L-DOPA that occur in this animal model in order to understand the actions of this compound in the context of the basal ganglia circuitry as a whole.