Dunwiddie T V, Diao L, Kim H O, Jiang J L, Jacobson K A
Program in Neuroscience, University of Colorado Health Science Center, Denver 80262, USA.
J Neurosci. 1997 Jan 15;17(2):607-14. doi: 10.1523/JNEUROSCI.17-02-00607.1997.
The adenosine A3 receptor is expressed in brain, but the consequences of activation of this receptor on electrophysiological activity are unknown. We have characterized the actions of a selective adenosine A3 receptor agonist, 2-chloro-N6-(3-lodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), and a selective A3 receptor antagonist, 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS 1191), in brain slices from rat hippocampus. In the CA1 region, activation of A3 receptors had no direct effects on synaptically evoked excitatory responses, long-term potentiation, or synaptic facilitation. However, activation of A3 receptors with Cl-IB-MECA antagonized the adenosine A1 receptor-mediated inhibition of excitatory neurotransmission. The effects of Cl-IB-MECA were blocked by pretreatment with MRS 1191, which by itself had no effect on A1 receptor-mediated responses. The presynaptic inhibitory effects of baclofen and carbachol, mediated via GABA(B) and muscarinic receptors, respectively, were unaffected by Cl-IB-MECA. The maximal response to adenosine was unchanged, suggesting that the primary effect of Cl-IB-MECA was to reduce the affinity of adenosine for the receptor rather than to uncouple it. Similar effects could be demonstrated after brief superfusion with high concentrations of adenosine itself. Under normal conditions, endogenous adenosine in brain is unlikely to affect the sensitivity of A1 receptors via this mechanism. However, when brain concentrations of adenosine are elevated (e.g., during hypoxia, ischemia, or seizures), activation of A3 receptors and subsequent heterologous desensitization of A1 receptors could occur, which might limit the cerebroprotective effects of adenosine under these conditions.
腺苷A3受体在大脑中表达，但该受体激活对电生理活动的影响尚不清楚。我们已经对选择性腺苷A3受体激动剂2-氯-N6-(3-碘苄基)-腺苷-5'-N-甲基脲酰胺（Cl-IB-MECA）和选择性A3受体拮抗剂3-乙基-5-苄基-2-甲基-4-苯基乙炔基-6-苯基-1,4-(±)-二氢吡啶-3,5-二羧酸酯（MRS 1191）在大鼠海马脑片中的作用进行了表征。在CA1区域，A3受体的激活对突触诱发的兴奋性反应、长时程增强或突触易化没有直接影响。然而，用Cl-IB-MECA激活A3受体可拮抗腺苷A1受体介导的兴奋性神经传递抑制。Cl-IB-MECA的作用可被MRS 1191预处理阻断，而MRS 1191本身对A1受体介导的反应没有影响。巴氯芬和卡巴胆碱分别通过GABA(B)和毒蕈碱受体介导的突触前抑制作用不受Cl-IB-MECA影响。对腺苷的最大反应未改变，这表明Cl-IB-MECA的主要作用是降低腺苷对受体的亲和力，而不是使其解偶联。用高浓度腺苷本身短暂灌流后也可观察到类似效应。在正常情况下，大脑中的内源性腺苷不太可能通过这种机制影响A1受体的敏感性。然而，当大脑中的腺苷浓度升高时（例如在缺氧、缺血或癫痫发作期间），可能会发生A3受体的激活以及随后A1受体的异源脱敏，这可能会限制这些情况下腺苷的脑保护作用。
