ADENOSINE AND MODULATION OF SYNAPTIC TRANSMISSION

描述：(研究人员摘要)腺苷是一种强有力的抑制性物质 中枢神经系统中突触传递的调节器。然而， 它的功能作用，特别是在正常的大脑活动中，仍然是 下定决心。目前的实验旨在定义这一角色，使用 研究腺苷对神经影响的电生理技术 大鼠脑内海马片的活动。第一组实验 将研究腺苷受体敏感性如何 受其他腺苷受体和代谢性谷氨酸的调节 感受器。初步研究表明，腺苷A3受体 激活会降低腺苷A1受体的敏感性，这个过程是 被假设为各种现象的基础，例如 腺苷在低氧条件下的超兴奋性保护作用。阻挡 通过这种机制使A1腺苷受体脱敏可能提供一种 增强腺苷在脑内的某些治疗作用的途径 缺血和缺氧。另一个主要焦点将放在生理事件上 产生细胞外嘌呤浓度的瞬时变化。 这些实验将识别和研究 释放腺苷或相关的嘌呤，如兴奋性突触 刺激、NMDA受体激活、腺苷环化酶激活，以及 缺氧。这些反应将与直接 嘌呤在药物中的应用选择性地影响对 将研究腺苷和嘌呤核苷酸，以及 这些药物与生理刺激释放的相互作用 我们将对嘌呤进行表征。 这项提案中详细介绍的研究应该能让我们深入了解 在这种情况下，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 受监管的。尽管腺苷受体拮抗剂，如咖啡因和 茶碱有一些治疗作用，你目前没有 使用腺苷受体的神经学或精神病学适应症 激动剂。将从计划中了解的基本信息 关于腺苷在神经系统中的作用的实验可能表明 这些药物可能的临床应用。

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.