MOLECULAR MECHANISMS OF LITHIUM ACTION IN AFFECTIVE ILLN

锂是最有效的精神药物治疗方法之一， 其作用机制尚不清楚。 最近的研究 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一个重要的过程。 介导细胞反应的主要分子事件和长期 调节几种神经递质受体，包括毒蕈碱 受体的 中枢毒蕈碱活性已被证明与 一种状态独立的临床倾向， 情节。 延长锂的临床治疗可降低 易受反复发作的情感影响 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。 的净结果 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 也来自对其他神经递质偶联PI系统的间接影响 影响大脑特定区域的胆碱能活动。 因此，在本发明中， 该提案旨在关注慢性锂对 调节动物边缘系统中的毒蕈碱受体 接受选择性药物/行为治疗策略。 这些策略旨在影响中枢毒蕈碱反应， 与当前关于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所有 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，按照 我们实验室以前的研究，在三个关键的功能水平： a）毒蕈碱受体亚型的结合特性; B）毒蕈碱受体亚型的结合特性; 激动剂偶联的PI反应;和c）蛋白激酶C的相关变化 活动 脑边缘区受体偶联的生化事件 大脑代表了对大脑进行实质性修饰潜在位点， 细胞/生理/行为功能。 这些长期的改变 由于产生的细胞内信号，两者都是有效的，并且 特异性，凭借所涉及的选择性受体亚型。 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，并导致更好地了解神经生物学基础， 这种混乱。

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.