Alcohol potently inhibits the kainate receptor-dependent excitatory drive of hippocampal interneurons
Alcohol potently inhibits the kainate receptor-dependent excitatory drive of hippocampal interneurons
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DOI：
10.1073/pnas.1137276100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Valenzuela, CF
中科院分区：
文献类型：
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作者：
Carta, M;Ariwodola, OJ;Valenzuela, CF
海人藻酸受体(KA-Rs)是谷氨酸门控的离子亲和性受体家族的一员，它还包括N-甲基-D-天冬氨酸(N-甲基-D-aspartate，N-甲基-D-天冬氨酸)和alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate(AMPA)受体。KA受体是海马区CA1区神经元间兴奋性的重要调节因子。这些受体的激活增强了神经元间的放电，从而有力地增加了锥体神经元中自发的抑制性突触后电流。我们在此报道，乙醇(Etoh)能有效地抑制这种KA-R介导的效应，其浓度低至仅摄入1-2杯饮料(5-10 mm)后血液中所能达到的水平。在AMPA和NMDA受体拮抗剂存在的情况下，加压红藻氨酸可引起中间神经元的去极化反应，从而触发重复动作电位放电。Roh有效地抑制了这些反应，达到足以消除动作电位放电的程度。这种效应似乎是Ka-Rs所特有的，因为乙醇不影响AMPA受体介导的去极化反应所触发的动作电位放电。重要的是，乙醇通过突触释放谷氨酸抑制神经元间动作电位的激活，以响应KA-R的激活，这表明我们的发现是生理学相关的。乙醇不影响KA-R依赖的谷氨酸释放对锥体神经元的调节。因此，乙醇通过抑制依赖KA-R的γ-氨基丁酸(GABA)能中间神经元的驱动，间接增加锥体神经元的兴奋性。我们推测，这种效应可以部分解释这种被广泛滥用的物质的一些自相矛盾的兴奋作用。一些人可能认为ROH的兴奋作用是积极的，这可能有助于酒精中毒的发展。
Kainate receptors (KA-Rs) are members of the glutamate-gated family of ionotropic receptors, which also includes N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. KA-Rs are important modulators of interneuron excitability in the CA1 region of the hippocampus. Activation of these receptors enhances interneuron firing, which robustly increases spontaneous inhibitory postsynaptic currents in pyramidal neurons. We report here that ethanol (EtOH) potently inhibits this KA-R-mediated effect at concentrations as low as those that can be achieved in blood after the ingestion of just 1-2 drinks (5-10 mM). Pressure application of kainate, in the presence of AMPA and NMDA receptor antagonists, evoked depolarizing responses in interneurons that triggered repetitive action potential firing. ROH potently inhibited these responses to a degree that was sufficient to abolish action potential firing. This effect appears to be specific for KA-Rs, as EtOH did not affect action potential firing triggered by AMPA receptor-mediated depolarizing responses. Importantly, EtOH inhibited interneuron action potential firing in response to KA-R activation by synaptically released glutamate, suggesting that our findings are physiologically relevant. KA-R-dependent modulation of glutamate release onto pyramidal neurons was not affected by EtOH. Thus, EtOH increases excitability of pyramidal neurons indirectly by inhibiting the KA-R-dependent drive of gamma-aminobutyric acid (GABA)ergic interneurons. We postulate that this effect may explain, in part, some of the paradoxical excitatory actions of this widely abused substance. The excitatory actions of ROH may be perceived as positive by some individuals, which could contribute to the development of alcoholism.