PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

该项目的目标是开发改进的药物疗法。 治疗特定的神经生成障碍，尤其是帕金森症 疾病和阿尔茨海默病。 左旋多巴治疗晚期高血压并发运动波动 饮食因素不能完全解释帕金森氏病 或体力活动。越来越多的证据表明，突触前 多巴胺神经元丢失是疲劳现象出现的原因 现象，而剂量-反应关系的陡化， 运动障碍阈值剂量的减少，并缩小了 左旋多巴的治疗窗，它的开关反应不足， 反映继发性突触后改变，可能涉及 D-1和D-2多巴胺受体介导的相互作用 机械装置。磨损现象完全缓解， 立即进行持续的多巴胺仿制疗法；开关 波动逐渐减弱。左旋多巴的作用能力 减少帕金森症状和诱发运动障碍似乎可以 反映了不同的药理机制。一种新的受控 释放剂型超过所有以前提供的口服制剂 左旋多巴制剂治疗运动波动患者。 在阿尔茨海默病中，(~3H)MK-801结合研究提示了变化 在一些承载NMDA受体的神经元中。所谓的NMDA受体 拮抗剂右美沙芬未能在大鼠体内提供 内源性兴奋性毒素喹啉的神经保护作用 酸。M1和M2受体激动剂的剂量没有 对阿尔茨海默病患者认知功能的影响 在实验中发现活跃的达到中心水平 动物。最大耐受量两个α-2肾上腺素受体 激动剂也没有表现出抗痴呆的效果。一种合成纤维 生长抑素激动剂在人类中枢神经系统中获得了一些进入 系统，但未能提高智力功能。

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.