Fedele E, Conti A, Raiteri M
Institute of Pharmacology and Pharmacognosy, University of Genova, Italy.
Neuropharmacology. 1997 Oct;36(10):1393-403. doi: 10.1016/s0028-3908(97)00112-3.
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 microM) was abolished by the NO synthase inhibitor L-NARG (100 microM) or the soluble guanylyl cyclase inhibitor ODQ (100 microM). 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 microM), the channel antagonist MK-801 (30 microM) or Mg2+ ions (1 mM). The AMPA/kainate receptor antagonists DNQX (100 microM) and NBQX (100 microM) abolished the WDS episodes but could not inhibit the cyclothiazide-evoked cGMP response. DNQX or NBQX (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 microM) 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.
在自由活动大鼠的脑内微透析过程中监测细胞外环磷酸鸟苷（cGMP），有助于研究谷氨酸受体/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。在无镁培养基中注入到大鼠海马体时，AMPA 优先受体脱敏阻滞剂环噻嗪会增加 cGMP 水平。环噻嗪（300 microM）的作用被 NO 合酶抑制剂 L-NARG（100 microM）或可溶性鸟苷酸环化酶抑制剂 ODQ（100 microM）消除。在注入环噻嗪期间，动物表现出一种惊厥前行为，其特征为频繁的“湿狗摇身”（WDS）。L-NARG 和 ODQ 均未减少 WDS 发作次数。用谷氨酸位点拮抗剂 CGS 19755（100 microM）、通道拮抗剂 MK-801（30 microM）或镁离子（1 mM）阻断 NMDA 受体功能，可预防环噻嗪引起的 cGMP 和 WDS 反应。AMPA/海人藻酸受体拮抗剂 DNQX（100 microM）和 NBQX（100 microM）消除了 WDS 发作，但不能抑制环噻嗪诱发的 cGMP 反应。DNQX 或 NBQX（但不是 MK-801）自身会升高细胞外 cGMP 水平。拮抗剂引发的 cGMP 反应似乎是由于阻止了谷氨酸依赖性抑制性γ-氨基丁酸（GABA）能张力，因为注入荷包牡丹碱（50 microM）会引起强烈的 cGMP 反应。结果表明：（a）海马体中与 NO/cGMP 途径相连的 AMPA/海人藻酸受体（而非 NMDA 受体）被内源性谷氨酸持续激活并保持脱敏状态；（b）环噻嗪对 AMPA/海人藻酸受体脱敏的阻断导致 NMDA 受体的内源性激活；（c）海马体 NO/cGMP 系统受到非 NMDA 离子型受体驱动的 GABA 能抑制性张力的影响；（d）观察到的惊厥前发作取决于海马体 NMDA 受体的激活，而非 NO 和 cGMP 的产生。
