ADENOSINE AND MODULATION OF SYNAPTIC TRANSMISSION

腺苷是中枢神经系统突触传递的有效调节剂， 神经系统，在某些情况下抑制反应的能力>95% 突触 然而，其职能作用的许多方面仍有待进一步研究。 测定 目前的实验将解决一些相关的 旨在使用电生理学技术定义这一角色的问题 研究腺苷对诱发兴奋性突触反应的影响 大脑切片的制备。 第一组实验将研究 腺苷阻断释放的细胞机制 神经递质在3兴奋性氨基酸能突触，即 海马CA 1区的Schaffer侧支/连合输入， 外侧嗅束输入到嗅觉皮层，皮层 输入到纹状体 佛波醇酯，锂， 将表征钾通道阻断剂对腺苷应答的影响。 第二组实验将使用贴片电极记录， 全细胞配置结合统计分析， 小EPSP的方差，以更好地定义 腺苷、其他神经调质和海马突触的拮抗剂。 第三组实验将集中在突触后的行动， 腺苷。 A2 a受体选择性激动剂CGS 21680的作用 将其特征在于在纹状体，“A1样”受体（可能A3？） 介导海马体中腺苷的突触后效应， 用受体亚型选择性药物进行研究， 腺苷激活的K+电流和腺苷调节的通道之间的关系 测定细胞内ATP（K+ [ATP]通道）。 最后， 将采用电生理学和药理学技术， 定量测定海马脑片对 腺苷，并研究调节细胞外 切片中腺苷的浓度。 本建议中详细介绍的研究应有助于我们了解 腺苷作用的受体， 介导腺苷反应，以及突触调制在 正常的大脑活动。 虽然腺苷受体拮抗剂， 咖啡因和茶碱有一定的治疗作用， 目前腺苷受体激动剂尚无临床用途。 基本 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可能的临床 这些药物的应用。

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.