PSYCHOPHARMACOLOGICAL EFFECTS OF EXOGENOUS CHOLINE

我们理解和治疗某些行为障碍的能力 大大受益于我们不断扩大的关于 单胺类神经递质的生物化学和药理学。 尽管大量证据表明，脑乙酰胆碱(ACh) 也与行为疾病有关，更不用说基本的 关于这个发射器的信息很少，如果有的话也很少 存在可长期给药以增强胆碱能的药物 中枢神经系统传输。我们的提案研究集中在一个糟糕的- 了解并可能是胆碱能神经元的独特方面，即， 他们使用胆碱作为ACh和这种膜的前体 磷脂，如磷脂酰胆碱(PC；卵磷脂)。 我们和其他人之前表明，补充胆碱可以 增加两种ACh的合成(特别是在频繁的- 神经元放电)和磷胆碱(PC的中间体 综合)。最近的研究表明，体内的胆碱 事实上，神经元PC被用于ACh的合成，当 胆碱供不应求，大脑将其用于此目的 优选地，以膜磷脂为代价。什么时候 大鼠纹状体超融合切片反复去极化 如果没有足够的外部胆碱，这台电脑就会耗尽，而且大多数 胆碱含量的一半将由释放的ACh来解释。 此外，其他主要的膜磷脂， 磷脂酰丝氨酸(PS)和磷脂酰乙醇胺(PE) 作为膜蛋白，也被耗尽，这表明 神经元去极化和膜水平之间的关系。这些 所有削减都可以通过以下方式阻止(并增强ACH释放) 在培养液中加入适量的胆碱。此外，胆碱的作用 可被胞苷或4-氨基吡啶增强，其 PS促进了神经元PC的整合。 拟议的研究检查生化机制，组织 这些变化的分布和功能后果 使用胆碱能细胞系(LAN-2；NG)的膜磷脂 108-15；PC-12)，超融合大鼠脑片，突触体，和 整只动物。我们还将继续研究(人脑) 样本)，这表明相关的异常发生在 阿尔茨海默病，并将决定精神药物是否 (可导致迟发性运动障碍)影响PC代谢 胆碱能神经元。

Our ability to understand and treat some behavioral disorders has benefitted greatly from our expanding knowledge about the biochemistry and pharmacology of monoamine neurotransmitters. Although abundant evidence indicates that brain acetylcholine (ACh) is also involved in behavioral diseases, much less basic information is available about this transmitter, and few if any drugs exists which can be given chronically to enhance cholinergic CNS transmission. Our proposal studies focus on a poorly- understood and perhaps-unique aspect of cholinergic neurons, i.e., their use of choline as a precursor for both ACh and such membrane phospholipids as phosphatidylcholine (PC; lecithin). We and others previously showed that supplemental choline could increase the syntheses of both ACh (particularly in frequently- firing neurons) and phosphocholine (an intermediate in PC synthesis). More recent studies have shown that the choline in neuronal PC is, in fact, used for ACh synthesis, and that, when choline is in short supply, the brain used it for this purpose preferentially, at the expense of membrane phospholipids. When superfused slices of rat striatum were depolarized repeatedly without adequate external choline, this PC was depleted, and most of its choline content would be accounted for by released ACh. Moreover, the other major membrane phospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), as well as membrane proteins, also were depleted, suggesting a relationship between neuronal depolarization and membrane levels. These reductions could all be blocked (and ACh release enhanced) by adding adequate choline to the medium. Moreover, choline's actions may be potentiated by cytidine or 4-aminopyridine, and its incorporation into neuronal PC enhanced by PS. Proposed studies examine the biochemical mechanisms, tissue distribution, and functional consequences of these changes in membrane phospholipids, using cholinergic cells lines (LAN-2; NG 108-15; PC-12), superfused rat brain slices, synaptosomes, and whole animals. We will also continue studies (on human brain samples) which suggest that related abnormalities occur in Alzheimer's disease, and will determine whether psychotropic drugs (which can cause tardive dyskinesia) affect PC metabolism in cholinergic neurons.