MOLECULAR MECHANISMS & LITHIUM ACTION--AFFECTIVE ILLNESS

锂是迄今为止最有效的精神药理疗法之一。 其作用机制尚不清楚。最近的研究表明 证明了锂在肌醇脂代谢中的作用部位 中枢神经系统。肌醇磷脂的水解也是一种 介导细胞反应和长期效应的主要分子事件 几种神经递质受体的调节，包括毒鼠强 受体。中枢性毒扁豆碱活动已被证明与 复发性情感性精神障碍的非状态临床易感性 剧集。延长锂的临床治疗可降低 易受反复情感发作的影响。我们建议，从长远来看 M受体调节的基本要素的适应性变化 可能有助于这种临床治疗效果。最终的结果是 锂对M受体活性的作用可能不仅源于 直接作用于毒扁豆碱/磷脂酰肌醇(PI)反应系统，但是 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， 这项建议旨在关注慢性锂对人体健康的影响 动物边缘系统中M受体的调节 接受选择性药物/行为治疗策略。 这些策略旨在通过以下方式影响中枢性毒鼠强反应 与当前有关易感性的临床概念一致 与躁狂/抑郁和锂的主要治疗作用有关。 受体反应性的改变可能发生在任何一个或全部 受体反应复合体的水平。因此，我们的实验 设计将检查毒碱受体的反应，根据 我们实验室以前的研究，在三个关键的功能水平上： A)M受体亚型的结合特性；b)M受体亚型 激动剂偶联的PI反应；以及c)蛋白激酶C的相关变化 活动。大脑皮层边缘区的受体偶联生化事件 大脑代表了大量修改的潜在位置 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 特定的，凭借涉及的选择性受体亚型。它是 预计这些调查将提供有关以下方面的基本知识 锂治疗复发性情感性精神障碍的作用机制 并有助于更好地了解糖尿病的神经生物学基础 这种紊乱。

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.