ADENOSINE AND MODULATION OF SYNAPTIC TRANSMISSION

描述：（研究者摘要）腺苷是一种有效的抑制剂， 中枢神经系统突触传递的调节剂。 但是，在这方面， 它的功能作用，特别是在正常的大脑活动中， 测定 目前的实验旨在定义这一作用，使用 电生理技术研究腺苷对神经元的作用 在大鼠脑海马切片中的活性。 第一组实验 将研究腺苷受体的敏感性可以被 由其他腺苷受体和代谢型谷氨酸调节 受体。 初步研究表明腺苷A3受体 激活降低腺苷A1受体的敏感性，这一过程是 假设是各种现象的基础，例如 腺苷在缺氧时对高兴奋性的保护作用。 阻断 通过这种机制使A1腺苷受体脱敏， 增强腺苷在脑中的某些治疗作用的方法 缺血和缺氧。 另一个主要焦点将是生理事件 产生细胞外嘌呤浓度的瞬时变化。 这些实验将识别和研究生理刺激， 释放腺苷或相关嘌呤，如兴奋性突触 刺激、NMDA受体活化、腺苷酸环化酶活化，以及 缺氧 这些反应将被比较，那些引起的直接 嘌呤类药物的应用以选择性地影响对 腺苷和嘌呤核苷酸将被研究， 这些试剂与生理刺激释放的 嘌呤将被表征。 本提案中详细介绍的研究应能提供有关如何 其中大脑中的腺苷受体在正常和 病理条件，以及细胞外腺苷水平如何 监管. 虽然腺苷受体拮抗剂如咖啡因和 茶碱有一些治疗作用，目前没有 腺苷受体的神经或精神适应症 激动剂 基本信息，将了解到，从拟议的 关于腺苷在神经系统中作用的实验可能表明， 这些药物的潜在临床应用。

DESCRIPTION: (Investigator's Abstract) Adenosine is a potent inhibitory modulator of synaptic transmission in the central nervous system. However, its functional role, particularly in normal brain activity, remains to be determined. The present experiments are aimed at defining this role, using electrophysiological techniques to study the effects of adenosine on neural activity in hippocampal slices form rat brain. The first set of experiments will investigate ways in which adenosine receptor sensitivity can be modulated by other adenosine receptors and by metabotropic glutamate receptors. Preliminary studies have shown that adenosine A3 receptor activation reduces adenosine A1 receptor sensitivity, and this process is hypothesized to underlie a variety of phenomena, such as the hyperexcitability protective effects of adenosine in hypoxia. Blocking the desensitization of A1 adenosine receptors via this mechanism may provide a way of enhancing some of the therapeutic actions of adenosine in brain ischemia and hypoxia. The other major focus will be on physiological events that produce transient changes in extracellular purine concentrations. These experiments will identify and study physiological stimuli which release adenosine or related purines, such as excitatory synaptic stimulation, NMDA receptor activation, activation of adenylyl cyclase, and hypoxia. These responses will be compared to those elicited by direct application of purines to agents to selectively affect responses to adenosine and to purine nucleotides will be investigated, and the interactions of these agents with physiologically stimulated release of purines will be characterized. The studies detailed in this proposal should provide insight into the ways in which adenosine receptors in the brain are activated under normal and pathological conditions, and how extracellular adenosine levels are regulated. Although adenosine receptor antagonists such as caffeine and theophylline have some therapeutic actions, thee are currently no neurological or psychiatric indications for the use adenosine receptor agonist. The basic information that will be learned from the proposed experiments about the role of adenosine in the nervous system might suggest possible clinical applications for these drugs.