BIOCHEMISTRY AND PHARMACOLOGY OF TRACE AMINES IN BRAIN

脑内微量胺的生物化学和药理学

• 批准号: 3375038
• 负责人: DAVID J EDWARDS
• 金额: $ 7.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 1988-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3375038
• 关键词: Parkinson's disease; amines; aminoacid metabolism; antidepressants; brain; brain metabolism; dopamine; gas chromatography; human tissue; mass spectrometry; octopamine; psychophysiology; urinalysis

The first goal of our proposal is to determine what proportion of various urinary amine metabolities in experimental animals originates in the central nervous system. The metabolites to be studied include the alcoholic metabolites of catacholamines and of trace amines. Concentrations of these metabolites will be determined simultaneously using gas chromatographic-mass spectrometric techniques which we have developed in our laboratory. Two metabolites of particular interest are 3,4-dihydroxyphenylethanol and p-hydroxyphenylglycol, metabolites of dopamine and octopamine, respectively, that we have identified and found to be present in significant quantities in rat brain and urine and in human urine. Our studies should provide a basis for using concentrations of various amine metabolites as useful indicators of the turnover rate of the corresponding amines in the brain of experimental animals as well as in human subjects, and for identifying possible disturbances in amine metabolism that may underlie or result from various psychiatric and neurological illnesses, such as depression and Parkinson's disease. The second goal is to apply these procedures to investigate the extent to which various amino acid precursors are converted to the corresponding amines. For example, we will determine to what extent the synthetic amino acid precursor of octopamine, p-hydroxyphenylserine, is converted to octopamine and its metabolities. These studies could indicate whether this amino acid may be used as a pharmacological tool to selectively increase octopamine formation, in order to elucidate its possible neurochemical role as well as its possible involvement in brain dysfunction. Finally, the effects of both acute and chronic administration of typical and atypical antidepressants on brain amine metabolism will be studied. In particular, we will test the notion that an increased level of octopamine or other trace amines is a common feature of diverse antidepressant agents and may serve as a trigger to the delayed effects of these drugs.

我们建议的第一个目标是确定不同的 实验动物尿胺代谢起源于 中枢神经系统。拟研究的代谢物包括 儿茶酚胺和微量胺的酒精代谢物。 这些代谢物的浓度将同时用 我们开发的气相色谱-质谱学技术 在我们的实验室里。两种特别感兴趣的代谢物是 3，4-二羟基苯乙醇和对羟基苯乙醇的代谢物 分别是多巴胺和章鱼胺，我们已经鉴定和发现 在大鼠脑、尿液和人类体内大量存在 尿液。我们的研究应该为使用浓度的 不同的胺类代谢物作为有效的指标的周转率 实验动物大脑中的相应胺以及 人体受试者，并用于识别胺中可能的干扰 新陈代谢可能是各种精神疾病和疾病的基础或结果 神经系统疾病，如抑郁症和帕金森氏症。这个 第二个目标是应用这些程序来调查 各种氨基酸前体被转化为相应的胺。 例如，我们将确定合成氨基酸在多大程度上 章鱼胺的前体对羟基苯丝氨酸转化为章鱼胺 及其新陈代谢。这些研究可能表明，这种氨基酸 可用作选择性增加章鱼胺的药理工具 形成，以阐明其可能的神经化学作用以及 它可能与大脑功能障碍有关。最后，它的影响 急性和慢性给药典型和非典型 抗抑郁药对脑胺代谢的影响将被研究。特别是， 我们将测试这样一种观点，即章鱼胺或其他物质水平的增加 微量胺是多种抗抑郁剂的共同特征，可能 是这些药物延迟作用的导火索。