MOLECULAR MECHANISMS OF LITHIUM ACTION IN AFFECTIVE ILLN

锂在情感疾病中作用的分子机制

• 批准号: 3380265
• 负责人: Robert H. Lenox
• 金额: $ 15.97万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3380265
• 关键词: antidepressants; atropine; bipolar depression; carbachol; cholinergic agents; disease /disorder model; drug metabolism; epinephrine; laboratory rat; limbic system; lipid metabolism; lithium; muscarinic receptor; neurotransmitter metabolism; phosphatidylinositols; protein kinase C; psychopharmacology; shock

Lithium is one of the most effective psychopharmacological treatments, yet the mechanism of its action remains unknown. Recent studies have demonstrated a site of action for lithium in inositol lipid metabolism in the central nervous system. Hydrolysis of the phosphoinositides is also a principal molecular event mediating the cellular response and long-term regulation of several neurotransmitter receptors, including the muscarinic receptor. Central muscarinic activity has been shown to be associated with a state-independent clinical predisposition to recurrent affective episodes. Extended clinical treatment with lithium reduces the vulnerability to recurrent affective episodes. We propose that long-term adaptive changes in essential elements of muscarinic receptor regulation may contribute to this clinical therapeutic effect. The net result of lithium's action on muscarinic receptor activity may stem not only from direct action on the muscarinic/phosphoinositide (PI) response system, but also from indirect effects on other neurotransmitter-coupled PI systems influencing cholinergic activity in specific regions of the brain. Thus, this proposal intends to focus upon the effects of chronic lithium on the regulation of the muscarinic receptor in the limbic system of animals undergoing selective pharmacological/behavioral treatment strategies. These strategies are designed to affect central muscarinic response in ways that are consistent with current clinical concepts regarding predisposition to mania/depression and the primary therapeutic actions of lithium. Alterations in receptor responsivity may take place at any one or all levels of the receptor response complex. Therefore, our experimental design will examine the muscarinic receptor response, in accordance with previous studies in our laboratory, at three critical levels of function: a) binding properties of muscarinic-receptor subtypes; b) muscarinic agonist-coupled PI response; and c) associated changes in protein kinase C activity. Receptor-coupled biochemical events in limbic regions of the brain represent potential sites for a substantial modification of cellular/physiological/behavioral function. These long-term alterations are both potent, by virtue of the generated intracellular signals, and specific, by virtue of the selective receptor-subtypes involved. It is expected that these investigations will provide basic knowledge regarding the mechanism of action of lithium in the treatment of recurrent affective illness and lead to a better understanding of the neurobiological basis of this disorder.

锂是最有效的精神药理学治疗方法之一，但 其作用机制仍不清楚。 最近的研究有 证明了锂在肌醇脂质代谢中的作用位点 中枢神经系统。 磷酸肌醇的水解也是 介导细胞反应和长期反应的主要分子事件 调节多种神经递质受体，包括毒蕈碱受体 受体。 中枢毒蕈碱活性已被证明与 复发性情感的独立于状态的临床倾向 剧集。 锂的长期临床治疗可减少 容易反复发作情感发作。 我们建议长期 毒蕈碱受体调节基本要素的适应性变化 可能有助于这种临床治疗效果。 最终结果为 锂对毒蕈碱受体活性的作用可能不仅源于 直接作用于毒蕈碱/磷酸肌醇（PI）反应系统，但是 也来自对其他神经递质耦合 PI 系统的间接影响 影响大脑特定区域的胆碱能活动。 因此， 该提案旨在重点关注长期锂对 动物边缘系统毒蕈碱受体的调节 接受选择性药物/行为治疗策略。 这些策略旨在以多种方式影响中枢毒蕈碱反应 与当前有关易感性的临床概念一致 躁狂/抑郁症和锂的主要治疗作用。 受体反应性的改变可能发生在任何一个或全部 受体反应复合物的水平。 因此，我们的实验 设计将检查毒蕈碱受体反应，根据 我们实验室之前的研究涉及三个关键的功能水平： a) 毒蕈碱受体亚型的结合特性； b) 毒蕈碱 激动剂耦合 PI 反应； c) 蛋白激酶 C 的相关变化 活动。 边缘区域的受体耦合生化事件 大脑代表了进行实质性修改的潜在位点 细胞/生理/行为功能。 这些长期的改变 凭借产生的细胞内信号，两者都是有效的，并且 特异性，取决于所涉及的选择性受体亚型。 这是 预计这些调查将提供有关 锂治疗复发性情感障碍的作用机制 疾病并导致更好地理解神经生物学基础 这种紊乱。