ALTERATIONS IN DOPAMINERGIC RESPONSE IN PARKINSONISM

左旋多巴对帕金森病的慢性治疗通常是 与运动波动和运动障碍的发展有关。这个 这些运动效应的原因尚不清楚，但有可能是这些 这些反应代表了对 慢性药物暴露引起的多巴胺能刺激。这 该提案将研究多巴胺能变化之间的关系。 反应和多巴胺能损害的程度、剂量和频率 多巴胺能兴奋和P物质含量的变化。 基底节中发现的被认为调节多巴胺能的多肽 神经传递。 甘彻博士研究了阿朴吗啡的药理作用 左旋多巴在帕金森病患者中的应用，有证据表明 多巴胺能耐受的存在。长期目标是 获得基础科学技术方面的培训，以便研究行为， 慢性脑损伤所致基底节的形态和生化变化 慢性治疗，开发更好的运动波动治疗方法 运动障碍。 这项提议将允许甘彻博士获得基础科学 开发自己的独立研究项目的技能和经验 将补充而不是重复现有的研究项目 上大学。生物化学和动物外科技术方面的培训将 在神经学家威廉·伍德沃德博士的监督下获得 在使用电化学检测和大脑的高效液相色谱方面具有专业知识 形态测量学。Gajanan Nilaver博士将在 免疫组织化学、脑成像和动物病变。约翰博士 酒精耐受性方面的权威克拉布将在 实验设计和解释。约翰·纳特医生，一位临床医生 神经药理学家和帕金森氏病专家将担任Dr。 甘彻的赞助商。俄勒冈健康科学大学及附属大学 各机构(Vollum Institute和波特兰退伍军人管理局)有一个主要的 对神经科学感兴趣，是一个强大的研究环境 其他合作研究。

The chronic treatment of Parkinson's disease with levodopa commonly is associated with the development of motor fluctuations and dyskinesias. The reason for these motor effects is unclear, but it is possible that these responses represent the development of tolerance and sensitization to dopaminergic stimulation resulting from chronic drug exposure. This proposal will examine the relationship between alterations in dopaminergic response and the degree of dopaminergic lesioning, the dose and frequency of dopaminergic stimulation, and changes in the content of substance P, a peptide found in the basal ganglia that is thought to modulate dopaminergic neurotransmission. Dr. Gancher has investigated the pharmacology of apomorphine and levodopa in patients with Parkinson's disease and has evidence to suggest the existence of dopaminergic tolerance. The long-term objectives are to obtain training in basic science techniques to allow studies of behavioral, morphological, and biochemical changes in the basal ganglia resulting from chronic treatment, to develop better treatments for motor fluctuations and dyskinesias. This proposal will allow Dr. Gancher to acquire basic science skills and experience to develop his own independent research program that will complement but not duplicate existing research programs at the university. Training in biochemical and animal surgical techniques will be obtained under the supervision of Dr. William Woodward, a neuroscientist with expertise in HPLC using electrochemical detection and brain morphometry. Dr Gajanan Nilaver will provide training in immunohistochemistry, brain mapping, and animal lesioning. Dr. John Crabbe, an authority on ethanol tolerance, will provide guidance in experimental design and interpretation. Dr. John Nutt, a clinical neuropharmacologist and expert in Parkinson's disease will serve as Dr. Gancher's sponsor. Oregon Health Sciences University and affiliated institutions (the Vollum Institute and the Portland VA) has a major interest in the neurosciences and is a robust research environment for additional collaborative studies.