PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

该项目的目标是开发改进的药物疗法 中枢神经系统疾病的基础上， 递质机制和临床功能。 调查的重点是 多巴胺系统和密切互动的神经通路，因为它们涉及到 痴呆和锥体外系疾病。 寻找发射器异常是关键 阿尔茨海默痴呆症的决定因素已经产生了证据， 胆碱能系统异常的重要性：胆碱 乙酰转移酶的减少在顶叶联合中并不明显 皮质，正电子发射断层扫描显示最大皮质 功能障碍，而不是在相对备用的额叶。 此外，委员会认为， 用最大耐受剂量的强效毒蕈碱激动剂治疗 未能改善认知能力。 另一方面，生长抑素 水平主要在后顶叶皮层降低。 神经肽 与生长抑素部分共定位的Y， 任何皮层区域。 运动波动，最终发生在大多数左旋多巴治疗 帕金森病患者，可能不反映周围的变化， 清除机制，而是药物诱导的中枢神经系统改变 药效学因素 机械（可穿戴输液泵）和 用于稳定的药物（缓释制剂） 血浆多巴水平被证明有效地减弱这些反应 波动 许多中枢介导的药理作用， 八肽胆囊收缩素（CCK-8）和相关肽给药， 啮齿动物现在似乎反映迷走神经传入的刺激。 的 然而，已经证明，外周注射CCK-8类似物 在非迷走神经切断的患者中治疗无效。 替代 因此，影响中枢胆囊收缩素能机制的策略是 正在探索，包括开发相对亲脂的 抑制金属内肽酶的化合物被发现负责初始的 CCK-8降解。

The goal of this project is to develop improved pharmaceutical therapies for central nervous system disease based on the relation between transmitter mechanisms and clinical function. Investigations focus on the dopamine system and closely interactive neural pathways as they relate to dementing and extrapyramidal disorders. The search for transmitter abnormalities which serve as critical determinants for Alzheimer dementia has yielded evidence casting doubt on the importance of cholinergic system abnormalities: choline acetyltransferase reductions were no greater in the parietal association cortex, where positron emission tomography shows maximum cortical dysfunction, than in the relatively spared frontal lobe. Moreover, treatment with maximum tolerated doses of a potent muscarinic agonist failed to improve cognitive performance. On the other hand, somatostatin levels were mainly reduced in the posterior parietal cortex. Neuropeptide Y, which is partially co-localized with somatostatin, was not abnormal in any cortical area. Motor fluctuations, which ultimately occur in most levodopa treated parkinsonian patients, probably do not reflect changes in peripheral clearance mechanisms but rather drug induced alterations in central pharmacodynamic factors. Both mechanical (wearable infusion pumps) and pharmaceutical (sustained release formulations) means for stabilizing plasma dopa levels are proving effective in attenuating these response fluctuations. Many of the centrally mediated pharmacological effects of peripherally administered cholecystokinin-octapeptide (CCK-8) and related peptides in rodents now appear to reflect stimulation of vagal afferents. The peripheral injection of CCK-8 analogs has, nevertheless, proven therapeutically ineffective in nonvagotomized patients. Alternate strategies for influencing central cholecystokininergic mechanisms are thus being explored, including the development of relatively lipophilic compounds to inhibit the metaloendopeptidase found responsible for initial CCK-8 degradation.