The glutamate receptor/NO/cyclic GMP pathway in the hippocampus of freely moving rats: Modulation by cyclothiazide, interaction with GABA and the behavioural consequences
The glutamate receptor/NO/cyclic GMP pathway in the hippocampus of freely moving rats: Modulation by cyclothiazide, interaction with GABA and the behavioural consequences
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DOI：
10.1016/s0028-3908(97)00112-3
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发表时间：
1997-10-01
影响因子：
4.7
通讯作者：
Raiteri, M
中科院分区：
文献类型：
--
作者：
Fedele, E;Conti, A;Raiteri, M
在自由活动的大鼠脑内微透析过程中监测细胞外cGMP允许研究谷氨酸受体/一氧化氮（NO）合酶/鸟苷酸环化酶途径中发生的功能变化以及这些变化与动物行为的关系。当在无Mg 2+培养基中注入大鼠海马时，环噻嗪（AMPA偏好受体脱敏的阻断剂）增加cGMP水平。环噻嗪（300 μ M）的作用被NO合酶抑制剂L-NARG（100 μ M）或可溶性鸟苷酸环化酶抑制剂ODQ（100 μ M）消除。在环噻嗪输注期间，动物表现出以频繁的“湿狗颤抖”（WDS）为特征的惊厥前行为。L-NARG和ODQ均未减少WDS发作。环噻嗪引起的cGMP和WDS反应均通过用谷氨酸位点拮抗剂CGS 19755（100 μ M）、通道拮抗剂MK-801（30 μ M）或Mg 2+离子（1 mM）阻断NMDA受体功能来阻止。AMPA/红藻氨酸受体拮抗剂DNQX（100 μ M）和NBQX（100 μ M）取消了WDS事件，但不能抑制环噻嗪诱发的cGMP反应。DNQX或NEQX（而不是MK-801）本身升高细胞外cGMP水平。由拮抗剂引起的cGMP反应似乎是由于阻止谷氨酸依赖性抑制性GABA能紧张，因为荷包牡丹碱（50 μ M）的输注引起了强烈的cGMP反应。结果表明：（a）海马中与NO/cGMP通路相关的AMPA/红藻氨酸受体（但不是NMDA受体）被内源性谷氨酸紧张性激活并保持在脱敏状态;（B）通过环噻嗪阻断AMPA/红藻氨酸受体脱敏导致NMDA受体的内源性激活;（c）海马NO/cGMP系统处于由非NMDA离子型受体驱动的GABA能抑制性紧张状态;（d）观察到的惊厥前发作依赖于海马NMDA受体激活，而不是NO和cGMP的产生。(C)1997年爱思唯尔科学有限公司
Monitoring of extracellular cGMP during intracerebral microdialysis in freely moving rats permits the study of the functional changes occurring in the glutamate receptor/nitric oxide (NO) synthase/guanylyl cyclase pathway and the relationship of these changes to animal behaviour. When infused into the rat hippocampus in Mg2+-free medium, cyclothiazide, a blocker of desensitization of the AMPA-preferring receptor, increased cGMP levels. The effect of cyclothiazide (300 mu M) was abolished by the NO synthase inhibitor L-NARG (100 mu M) or the soluble guanylyl cyclase inhibitor ODQ (100 mu M). During cyclothiazide infusion the animals displayed a pre-convulsive behaviour characterized by frequent ''wet dog shakes'' (WDS). Neither L-NARG nor ODQ decreased the WDS episodes. Both cGMP and WDS responses elicited by cyclothiazide were prevented by blocking NMDA receptor function with the glutamate site antagonist CGS 19755 (100 mu M), the channel antagonist MK-801 (30 mu M) or Mg2+ ions (1 mM). The AMPA/kainate receptor antagonists DNQX (100 mu M) and NBQX (100 mu M) abolished the WDS episodes but could not inhibit the cyclothiazide-evoked cGMP response. DNQX or NEQX (but not MK-801) elevated, on their own, extracellular cGMP levels. The cGMP response elicited by the antagonists appears to be due to prevention of a glutamate-dependent inhibitory GABAergic tone, since infusion of bicuculline (50 mu M) caused a strong cGMP response. The results suggest that (a) AMPA/kainate receptors linked to the NO/cGMP pathway in the hippocampus (but not NMDA receptors) are tonically activated and kept in a desensitized state by endogenous glutamate; (b) blockade of AMPA/kainate receptor desensitization by cyclothiazide leads to endogenous activation of NMDA receptors; (c) the hippocampal NO/cGMP system is under a GABAergic inhibitory tone driven by non-NMDA ionotropic receptors; (d) the pre-convulsive episodes observed depend on hippocampal NMDA receptor activation but not on NO and cGMP production. (C) 1997 Elsevier Science Ltd.