MECHANISMS AND REGULATION OF 5-HT RECEPTORS IN THE CNS

在过去的十年中，特别是在引入 体外结合技术，取得了相当大的进展， 了解血清素受体的类型， 中枢神经系统 尽管有这些进步， 近年来，人们对脑电活动的认识还不多， 由大脑中的这些受体介导， 机制等 在过去的几年里， 关于其中一个的行动和机制， 5-HT 1A受体。 然而，我们所知甚少 关于另一个人的电生理行为和机制 脑内5-HT受体及其调控机制的研究进展 中枢肾上腺素能反应性。 因此，本申请 建议使用细胞内记录来检查这些问题 海马体和前额叶的体外脑切片 扣带回皮质，两个区域富含不同类型的5-HT 结合位点。 在第一系列实验中，将利用 先前的知识和经验获得的5-HT 1A反应， 海马体来检查调节的潜在机制 受体的敏感性，以及 突触释放的5-HT。 具体来说，腺苷酸 环化酶抑制和肌醇磷脂在 将确定该区域中受体敏感性的调节， 以及慢性抗抑郁治疗可能 通过作用于5-HT受体改变5-HT反应性， 将测试肌醇磷脂。 此外， 海马中存在的不同5-HT受体介导 将确定突触释放的5-HT的作用。 后来，在第二个系列的实验中， 与其他5-HT受体相关的机制将被检查 通过记录前扣带皮层来识别和 表征5-HT 2和5-HT 1C受体介导的作用 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-HT在大脑中作用的理解， 中枢5-HT受体的分子药理学。 此外还 也希望这些基础研究能有助于更好地 了解一般的受体调节和前额叶 特别是大脑皮层，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.