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 Mg 2+ -free medium, cyclothiazide, a blocker of desensitization of the AMPA-preferring receptor, increased cGMP levels. The effect of cyclothiazide (300 μM) was abolished by the NO synthase inhibitor l -NARG (100 μM) or the soluble guanylyl cyclase inhibitor ODQ (100 μM). 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 μM), the channel antagonist MK-801 (30 μM) or Mg 2+ ions (1 mM). The AMPA/kainate receptor antagonists DNQX (100 μM) and NBQX (100 μM) 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 glutamatedependent inhibitory GAB Aergic tone, since infusion of bicuculline (50 μM) 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. © 1997 Elsevier Science Ltd.
Neuropharmacology – Elsevier
Published: Oct 1, 1997
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