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Modulation of cyclothiazide on the glutamate receptor/NO/cyclic GMP pathway in the hippocampus of freely moving rats

The effects of cyclothiazide on the glutamate receptor/NO/cGMP pathway were determined by in vivo microdialysis in the rat hippocampus. The local infusion of cyclothiazide, a blocker of α amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid (AMPA) receptor desensitization, in a Mg 2+ free medium, elicited the elevation of cGMP levels. The effect of cyclothiazide was abolished by a NO synthase inhibitor N G nitro L arginine (L NNA) or the selective inhibitor of soluble guanylyl cyclase 1H oxadiazoloquinoxaline 1 one (ODQ). During cyclothiazide infusion, the rat displayed a pre convulsive behavior characterised by frequent “wet dog shakes (WDS)”. Neither L NNA nor ODQ decreased significantly the numbers of WDS episodes. Both cGMP elevation and WDS response elicited by cyclothiazide were prevented by the channel antagonist of N methyl D aspartic acid (NMDA) receptors dizocilpine (MK 801) or Mg 2+ ions. The AMPA/kainate receptor antagonists 6,7 dinitroquinoxaline 2,3 dione (DNQX) and 6 nitro 7 sulphamoylbenzo(f)quinoxaline 2,3 dione(NBQX) abolished the WDS episodes but could not inhibit the cyclothiazide evoked cGMP response. These results indicate that (a) AMPA receptors linked to the NO cGMP pathway in the hippocampus keep in a desensitized state by endogenous glutamate; (b) the blockade of AMPA receptor desensitization by cyclothiazide leads to the endogenous activation of NMDA receptors.