PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

该项目的目标是开发改进的药物疗法。 对于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 多巴胺系统及其密切相互作用的神经通路 精神错乱和锥体外系障碍。 寻找作为关键的发射器异常 阿尔茨海默病的决定因素已经产生了证据，令人怀疑 胆碱能系统异常的重要性：胆碱 在顶叶联合中，乙酰转移酶的降低并不明显。 皮质，正电子发射断层扫描显示最大皮质 功能障碍，而不是相对安全的额叶。此外， 使用最大耐受量的强效M受体激动剂治疗 未能提高认知能力。另一方面，生长抑素 表达水平主要在后顶叶皮质降低。神经肽 与生长抑素部分共定位的Y基因在 任何皮质区域。 运动波动，最终发生在大多数接受左旋多巴治疗的患者 帕金森氏症患者，可能没有反映外周的变化 清除机制，而不是药物诱导的中枢改变 药效学因素。机械式(可穿戴输液泵)和 药物(缓释制剂)稳定的手段 血浆多巴水平被证明能有效地减弱这些反应。 波动。 许多中枢调节的外周药理作用 八肽缩胆囊素(CCK-8)及相关多肽对小鼠的影响 啮齿动物现在似乎反映了迷走神经传入的刺激。这个 然而，外周注射CCK-8类似物已被证明 对未切断迷走神经的患者治疗无效。替代方案 因此，影响中枢缩胆囊素能机制的策略 正在探索中，包括相对亲脂性的开发 化合物，以抑制金属内肽酶，发现负责初始 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.