ALTERATIONS IN DOPAMINERGIC RESPONSE IN PARKINSONISM

帕金森症多巴胺能反应的改变

• 批准号: 2259442
• 负责人: STEPHEN T GANCHER
• 金额: $ 9.4万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2259442
• 关键词: Parkinson's disease; abnormal involuntary movement; antiparkinson drugs; apomorphine; basal ganglia; brain metabolism; clinical trials; degenerative motor system disease; dihydroxyphenylalanine; dopamine; dosage; drug administration rate /duration; drug adverse effect; drug metabolism; drug tolerance; experimental brain lesion; human subject; immunocytochemistry; in situ hybridization; laboratory rat; microdialysis; neuromuscular transmission; optical rotation; pharmacokinetics; radioimmunoassay; stimulant /agonist; stimulus /response; substance P

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.

帕金森病的长期治疗与左旋多巴通常是 与运动波动和运动障碍的发展有关。 的 这些运动效应的原因尚不清楚，但有可能是这些 这些反应代表着对下列问题的容忍和敏感的发展： 由长期药物暴露引起的多巴胺能刺激。 这 这项提案将研究多巴胺能神经元的改变与 反应和多巴胺能损害的程度，剂量和频率 多巴胺能刺激，以及P物质，a 在基底神经节中发现的一种肽，被认为调节多巴胺能 神经传递 甘彻博士研究了阿扑吗啡的药理学， 左旋多巴治疗帕金森病，有证据表明 多巴胺耐受的存在。 长期目标是 获得基础科学技术的培训，以便研究行为， 基底神经节的形态学和生化变化， 慢性治疗，以开发更好的治疗运动波动， 运动障碍 这项提案将使甘彻博士获得基础科学 技能和经验，发展自己的独立研究计划， 将补充但不重复现有的研究计划， 大学 生物化学和动物外科技术的培训将在 在神经科学家威廉·伍德沃德博士的监督下获得 拥有使用电化学检测和大脑的HPLC专业知识 形态测量学 Gajanan Nilaver博士将提供以下培训： 免疫组织化学、脑映射和动物损伤。 Dr. John Crabbe是乙醇耐受性方面的权威，他将提供以下指导： 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病专家将担任博士。 甘彻的担保人 俄勒冈州健康科学大学及附属大学 机构（Vollum研究所和波特兰VA）有一个主要的 对神经科学感兴趣，是一个强大的研究环境， 额外的合作研究。