NEUROPHARMACOLOGY OF COGNITION AND MOOD IN GERIATRIC NEUROPSYCHIATRY

老年神经精神病学中认知和情绪的神经药理学

• 批准号: 5203652
• 负责人: T SUNDERLAND
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5203652
• 关键词: Alzheimer's disease; MAO inhibitors; aging; amyloid proteins; anticholinergic agent; brain disorder chemotherapy; brain disorder diagnosis; cognition; combination chemotherapy; dosage; emotions; human old age (65+); human subject; human therapy evaluation; muscarinic receptor; neural degeneration; neuropharmacology; perfusion; psychometrics; psychopharmacology; scopolamine; serotonin inhibitor; single photon emission computed tomography

Research in the Section on Geriatric Psychiatry (SGP) has focused on three main areas: clinical studies of depression and Alzheimer's disease (AD), the pharmacologic modelling of cognition, and the underlying mechanisms of neurodegeneration in AD. With treatment-resistant elderly depressives, work has been published showing that selegiline, a monoamine oxidase inhibitor known mostly for its usefulness with Parkinson's disease, is also effective with older depressives, but only at high doses which inhibit both the MAO-A as well as the MAO-B subtype of the enzyme. In an innovative study of AD patients and age-matched controls, cerebral perfusion and muscarinic receptor labelling was tested with single photon emission computerized tomography (SPECT) scans before and after scopolamine was administered chronically, and it was determined that AD subjects revealed divergent responsivity when compared to the controls. Specifically, the chronic scopolamine treatment led to evidence of increased perfusion in the elderly controls whereas, the AD subjects showed a significant increase in the ratio of muscarinic binding to perfusion following the drug phase compared to the elderly normals, suggestive of differential cholinergic upregulation in these two groups. In pharmacologic modelling studies with normal elderly subjects, it was demonstrated that manipulation of the cholinergic system with m-CPP, a mixed serotonergic agonist/antagonist, could further exacerbate the deficits generated by anticholinergics alone; however, ondansetron, a 5- HT3 antagonist purported to improve memory in selected animal experiments, was not associated with a dampening of the scopolamine- induced memory impairment. Finally, with respect to the basic mechanisms of AD neurotoxicity, we have discovered that the beta amyloid peptide (abeta) may be a functional growth factor. Operating via a tyrosine kinase mediated pathway, abeta regulates processes as diverse as platelet aggregation and neurite outgrowth. Low levels of abeta are soluble and can utilize this mechanism while higher levels tend to aggregate and produce toxicity. APO E modulates abeta formation with the various APO E isozymes acting differently in this process. Further characterization of these mechanisms may well lead to novel strategies for blocking abeta toxicity in vitro and eventually in clinical experiments with AD subjects.

老年精神病学（SGP）部分的研究重点是 三个主要领域：抑郁症和阿尔茨海默氏病的临床研究 （AD），认知的药理学建模和基础 AD中神经退行性的机理。 与耐药的老年人 沮丧的人，已经出版了作品，表明单胺SSelegiline 氧化酶抑制剂主要以其对帕金森氏症的有用性而闻名 疾病，也可以在较旧的抑郁症中有效，但仅在高剂量下 抑制酶的MAO-A和MAO-B亚型。 在一项针对AD患者和年龄匹配对照的创新研究中，大脑 用单个光子测试了灌注和毒蕈碱受体标记 排放计算机断层扫描（SPECT）扫描之前和之后 骨pol碱是长期施用的，并确定AD 与对照组相比，受试者揭示了反应性不同。 具体而言，慢性孢子胺治疗导致了 老年人对照组的灌注增加，而广告受试者 显示毒蕈碱结合与 与老年人相比，在药物期之后的灌注， 暗示这两组中胆碱能的差异上调。 在正常老年受试者的药理建模研究中，是 证明用M-CPP（A）操纵胆碱能系统 混合血清素能激动剂/拮抗剂可能会进一步加剧 仅抗胆碱药产生的缺陷；但是，ondansetron，一个5- HT3拮抗剂据称可以改善选定动物的记忆力 实验与Scopolamine-的衰减无关 诱导记忆力障碍。 最后，关于基本机制 AD神经毒性，我们发现β淀粉样蛋白肽 （ABETA）可能是功能生长因子。 通过酪氨酸操作 激酶介导的途径，Abeta调节与血小板一样多样化的过程 聚集和神经突生长。 低水平的Abeta可溶性和 可以利用这种机制，而较高的水平倾向于聚集和 产生毒性。 APO E使用各种AP​​O调节Abeta组 E在此过程中起作用的E同工酶不同。 进一步的表征 这些机制很可能会导致阻止Abeta的新型策略 体外毒性，最终在AD的临床实验中 主题。