ADENOSINE AND MODULATION OF SYNAPTIC TRANSMISSION

腺苷和突触传递的调节

• 批准号: 2267427
• 负责人: THOMAS V DUNWIDDIE
• 金额: $ 11.67万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2267427
• 关键词: GABA receptor; adenosine; adenosinetriphosphatase; brain electrical activity; calcium; corpus striatum; evoked potentials; glutamates; hippocampus; inhibitor /antagonist; laboratory rat; lithium; magnesium; muscarinic receptor; neural information processing; neural transmission; neuropeptide receptor; neuropharmacology; neurotransmitter receptor; neurotransmitters; olfactory lobe; phorbols; potassium; potassium channel; pyramidal cells; receptor binding; slow potential; statistics /biometry; stimulant /agonist; synapses; theophylline; voltage /patch clamp

Adenosine is a potent modulator of synaptic transmission in the central nervous system, with the capability of inhibiting responses by >95% at some synapses. However, many aspects of its functional role remain to be determined. The present experiments will address a number of related issues aimed at defining this role, using electrophysiological techniques to study the effects of adenosine on evoked excitatory synaptic responses in brain slice preparations. The first set of experiments will investigate the cellular mechanism(s) by which adenosine blocks the release of neurotransmitter at 3 excitatory amino acidergic synapses, namely the Schaffer collateral/commissural input to the CA1 region of the hippocampus, the lateral olfactory tract input to the olfactory cortex, and the cortical input to the striatum. The effects of phorbol ester, lithium, and potassium channel blockers on responses to adenosine will be characterized. The second set of experiments will use patch electrode recording in the whole-cell configuration in combination with a statistical analysis of the variance in small EPSPs to better define the effects and site of action of adenosine, other neuromodulators, and antagonists at hippocampal synapses. The third set of experiments will focus on the postsynaptic actions of adenosine. The effects of the A2a receptor-selective agonist CGS 21680 will be characterized in striatum, the "A1-like" receptors (possibly A3?) that mediate the postsynaptic effects of adenosine in the hippocampus will be studied with receptor subtype selective drugs, and the relationship between K+ currents activated by adenosine and channels regulated by intracellular ATP (K+ [ATP] channels) will be determined. Finally, electrophysiological and pharmacological techniques will be employed to quantitatively determine the sensitivity of hippocampal slices to adenosine, and investigate the factors that regulate the extracellular concentration of adenosine in the slice. The studies detailed in this proposal should improve our understanding of the receptors upon which adenosine acts, the cellular mechanisms that mediate adenosine responses, and the role played by synaptic modulation in normal brain activity. Although adenosine receptor antagonists such as caffeine and theophylline have some therapeutic actions, there are currently no clinical uses for adenosine receptor agonists. 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.

腺苷是中枢神经系统突触传递的有力调节剂。 神经系统，在某些情况下抑制反应的能力为95% 突触。然而，它的职能作用的许多方面仍有待于 下定决心。目前的实验将涉及一些相关的 旨在使用电生理技术定义这一角色的问题 腺苷对兴奋性突触反应的影响 在脑片准备中。第一组实验将调查 腺苷阻断钙离子释放的细胞机制(S) 3种兴奋性氨基酸能突触的神经递质，即 Schaffer侧支/连合传入海马区CA1区， 侧嗅束输入到嗅皮层，皮质 输入到纹状体。佛波酯、锂和 钾通道阻滞剂对腺苷的反应将被描述。 第二组实验将使用贴片电极记录 结合统计分析的全细胞构型 小EPSP中的差异，以更好地定义影响和作用部位 腺苷、其他神经调节剂和海马突触的拮抗剂。 第三组实验将集中在突触后的动作。 腺苷。A2a受体选择性激动剂CGS 21680的作用 将纹状体中的“A1样”受体(可能是A3？) 在海马区介导腺苷的突触后效应 与受体亚型选择性药物的研究及其关系 腺苷激活的K+电流与受 将测定细胞内ATP(K+[ATP]通道)。最后， 将使用电生理和药理学技术来 定量测定大鼠海马片对脑组织损伤的敏感性 腺苷，并研究调节细胞外的因素 切片中腺苷的浓度。 这项建议中详述的研究应该会提高我们对 腺苷作用于的受体，细胞机制 介导腺苷反应，以及突触调节在脑内的作用 大脑活动正常。尽管腺苷受体拮抗剂如 咖啡因和茶碱有一些治疗作用，有 目前尚无腺苷受体激动剂的临床应用。最基本的 将从拟议的实验中了解到的关于 腺苷在神经系统中的作用可能提示临床 这些药物的申请。