MECHANISMS AND REGULATION OF 5-HT RECEPTORS IN THE CNS

在过去的十年中，特别是在引入in之后 体外结合技术，已经取得了相当大的进展 了解体内存在的5-羟色胺受体类型 中枢神经系统。尽管有这些进步，直到 目前，对其电生理行为知之甚少。 由大脑中的这些受体及其潜在的 机械装置。在过去的几年里，取得了实质性的进展 已经就其中一个的行动和机制做出了规定 受体，5-HTlA受体。然而，我们仍然知之甚少。 关于另一种的电生理作用和机制 大脑中的5-羟色胺受体及其调控机制 中枢5-羟色胺能反应。因此，此应用程序 建议使用细胞内录音来研究这些问题 海马区和大脑前叶的体外脑片 扣带回皮质，两个区域富含不同类型的5-羟色胺 结合部位。 在第一系列实验中，我们将利用 以前在5-HTlA响应方面获得的知识和经验 海马体来研究这种调节的机制 受体在这一区域的敏感性及其作用 突触释放5-羟色胺。具体地说，腺苷的作用 环化酶抑制和肌醇磷脂在细胞周期中的作用 这一区域受体敏感性的调节将被确定， 还有一种假设，即慢性抗抑郁药物治疗可能 通过作用于偶联的5-羟色胺受体改变5-羟色胺的反应性 肌醇磷脂将进行测试。此外，还包括 海马区不同的5-羟色胺受体在介导 突触释放的5-羟色胺的作用将被确定。 后来，在第二系列实验中，动作和 与其他5-羟色胺受体相关的机制将被研究。 通过在前扣带回皮质记录来识别和 5-HT2和5-HT1C受体介导的作用特征 并确定它们的离子和分子 行动机制。 预计这些研究将大大有助于 我们对5-羟色胺在大脑中的作用和 中枢5-羟色胺受体的分子药理学。此外，它还 也希望这些基础研究将有助于更好地 对受体调节的总体和前额叶的理解 尤其是皮质，并将提出新的治疗方法 用于治疗精神疾病。

During the past decade, especially after the introduction of in vitro binding techniques, considerable progress has been made in understanding the types of serotonin receptors present in the central nervous system. In spite of these advances, until recently, little was known about the electrophysiological actions mediated by these receptors in the brain and their underlying mechanisms. During the past few years, substantial advances have been made regarding the actions and mechanism of one of the receptors, the 5-HTlA receptor. Yet, very little is still known about the electrophysiological actions and mechanisms of the other 5-HT receptors in the brain and about the mechanisms controlling central serotonergic responsiveness. Therefore, this application proposes to examine these questions using intracellular recordings in vitro brain slices from the hippocampus and the anterior cingulate cortex, two areas enriched in different types of 5-HT binding sites. In a first series of experiments, advantage will be taken of previous knowledge and experience gained with 5-HTlA responses in the hippocampus to examine the mechanisms underlying the regulation of receptor sensitivity in this area and the actions of synaptically released 5-HT. Specifically, the role adenylate cyclase inhibition and inositol phospholipids play in the regulation of receptor sensitivity in this area will be determined, and the hypothesis that chronic antidepressant treatment might change 5-HT responsiveness by acting on 5-HT receptors coupled to inositol phospholipids will be tested. In addition, the role of the different 5-HT receptors present in hippocampus in mediating the effects of synaptically released 5-HT will be determined. Later, in a second series of experiments, the actions and mechanisms associated with other 5-HT receptors will be examined by recording in the anterior cingulate cortex to identify and characterize the actions mediated by the 5-HT2 and 5-HT1C receptors present in this area and to determine their ionic and molecular mechanisms of action. It is expected that these studies will significantly contribute to our understanding of the actions of 5-HT in the brain and the molecular pharmacology of central 5-HT receptors. In addition, it is also hoped that these basic studies will contributed to a better understanding of receptor regulation in general and the prefrontal cortex in particular and will suggest new therapeutic approaches for the treatment of mental diseases.