PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

该项目的目标是开发更好的药物疗法 治疗特定的神经再生障碍，尤其是帕金森病 疾病和阿尔茨海默病。 左旋多巴治疗晚期乳腺癌并发的运动波动 帕金森病不能完全由饮食因素解释 或体力活动。 越来越多的证据表明，突触前 多巴胺神经元的缺失是导致 现象，而剂量反应关系的陡峭化， 减少运动障碍阈值剂量，并缩小 左旋多巴的治疗窗口，其是开-关反应的基础， 反映继发性突触后变化，可能涉及 D-1和D-2多巴胺受体介导的相互作用 机制等 磨损现象完全缓解， 立即连续多巴胺类药物治疗;开-关 波动逐渐减弱。 左旋多巴能够 减少帕金森症状和诱发运动障碍， 反映了不同的药理学机制。 一个新的控制 释放制剂超过了所有以前可用的口服 左旋多巴制剂治疗运动波动患者。 在阿尔茨海默病中，（3 H）MK-801结合研究表明， 在一些NMDA受体轴承神经元。 所谓的NMDA受体 拮抗剂美沙芬在大鼠中未能提供 对内源性兴奋性毒素、喹啉类 酸 M1和M2毒蕈碱受体激动剂的剂量没有 对阿尔茨海默病患者认知能力的影响， 达到中央水平发现活跃在实验 动物 最大耐受剂量两种α-2肾上腺素受体 激动剂也没有表现出抗痴呆功效。 合成 一种生长抑素激动剂进入了人类中枢神经系统 系统，但未能改善智力功能。

The goal of this project is to develop improved pharmacotherapies for selected neurodgenerative disorder, especially Parkinson disease and Alzheimer disease. Motor fluctuations complicating levodopa therapy of advanced Parkinsons disease could not be fully explained by dietary factors or physical activity. Mounting evidence suggested that presynaptic dopamine neuron loss accounts for the appearance of wearing-off phenomena, while a steepening of the dose-response relation, a reduction in the dyskinesia threshold dose, and a narrowing of the therapeutic window for levodopa, which underly on-off responses, reflect secondary postsynaptic changes, possibly involving interactions between D-1 and D-2 dopamine receptor mediated mechanisms. Wearing-off phenomenon remitted completely and immediately with continuous dopaminomimetic therapy; on-off fluctuations gradually diminished. The ability of levodopa to reduce parkinsonian signs and to induce dyskinesias appeared to reflect distinct pharmacologic mechanisms. A new controlled release formulation surpassed all previously available oral levodopa preparation in patients with motor fluctuations. In Alzheimers disease, (3H)MK-801 binding studies suggested changes in some NMDA receptor bearing neurons. The purported NMDA receptor antagonist, dextromethorphan, failed in rats to provide neuroprotection against the endogenous excitotoxin, quinolinic acid. Doses of an M1 and M2 muscarinic receptor agonist had no effect on cognitive performance in Alzheimer patients despite attainment of central levels found active in the experimental animal. Maximally tolerated doses two alpha-2 adrenoceptor agonists also exhibited no antidementia efficacy. A synthetic somatostain agonist gained some entry in the human central nervous system, but failed to improve intellectual function.