Extracellular adenosine concentrations in hippocampal brain slices and the tonic inhibitory modulation of evoked excitatory responses.
Extracellular adenosine concentrations in hippocampal brain slices and the tonic inhibitory modulation of evoked excitatory responses.
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发表时间：
1994-02
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通讯作者：
T. Dunwiddie;Liping Diao
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作者：
T. Dunwiddie;Liping Diao
由于腺苷被脑组织快速摄取和代谢，因此很难确定其真正的药理效力，也很难确定腺苷在脑组织中的基本细胞外浓度。在目前的研究中，我们使用几种独立的药理学方法来估计这些参数，使用腺苷介导的对大鼠海马片CA1区场兴奋性突触后电位的抑制作为生物反应。实验用潘生丁和S-(4-硝基苄基)-6-硫代肌苷抑制腺苷摄取，竞争性腺苷受体拮抗剂使腺苷量效曲线右移，并校正内源性腺苷对量效曲线的影响。提示腺苷抑制场兴奋性突触后电位的EC50在600~760 nM之间。然后从腺苷受体拮抗剂灌流引起的反应中估计脑片的基础细胞外腺苷浓度。对平均内源性细胞外腺苷浓度的估计在140到200 nM的范围内，尽管对单个切片的估计有很大的差异。这些值属于基于微透析研究的完整脑组织中腺苷细胞外浓度的估计范围，但显著低于使用生化技术测量脑组织中的腺苷总量的估计值；这表明组织中的相当大一部分腺苷处于与细胞外空间不直接通信的隔室中。
Because adenosine is taken up rapidly and metabolized by brain tissue, it has been difficult to establish its true pharmacological potency and, for similar reasons, to determine the basal extracellular concentrations of adenosine in brain. In the present studies, we used several independent pharmacological approaches to estimate these parameters, using the adenosine-mediated inhibition of the field excitatory postsynaptic potential evoked in the CA1 region of rat hippocampal slices as the biological response. The experiments used dipyridamole and S-(4-nitrobenzyl)-6-thioinosine to inhibit adenosine uptake, competitive adenosine receptor antagonists to shift adenosine dose response curves to the right, and corrected for the effect of endogenous adenosine on dose-response curves. These approaches suggested that the EC50 for adenosine for depressing field excitatory postsynaptic potentials is in the range of 600 to 760 nM. Basal extracellular adenosine concentrations in brain slices were then estimated from the responses induced by superfusion with adenosine receptor antagonists. The estimates for the mean endogenous extracellular adenosine concentrations were in the range of 140 to 200 nM, although there was substantial variation in estimates for individual slices. These values fall within the range of estimated extracellular concentrations of adenosine in intact brain based on microdialysis studies, but are significantly below those estimated using biochemical techniques for measurement of total adenosine in brain tissue; this suggests that a substantial fraction of tissue adenosine is in a compartment that does not communicate directly with the extracellular space.