CYCLOTHIAZIDE ACTS AT A SITE ON THE ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONIC-ACID RECEPTOR COMPLEX THAT DOES NOT RECOGNIZE COMPETITIVE OR NONCOMPETITIVE AMPA RECEPTOR ANTAGONISTS

Activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of ionotropic glutamate receptors by certain agon ists, including AMPA and glutamate, has been shown to result in a rapi d desensitization of the receptor. This desensitization is profoundly inhibited by the benzothiadiazide diuretic, cyclothiazide. We previous ly reported that cyclothiazide potentiates AMPA-induced [H-3]norepinep hrine ([H-3]NE) release from rat hippocampal slices. We used this syst em to investigate the possible interaction of cyclothiazide with vario us AMPA receptor antagonists, including the competitive antagonist LY2 93558 and the 2,3-benzodiazepine noncompetitive antagonist GYKI 53655. Cyclothiazide significantly potentiated both AMPA- and KA-induced [H- 3]NE release from slices of the rat hippocampus. LY293558 and GYKI 536 55 inhibited the potentiated and nonpotentiated AMPA- and KA-induced [ H-3]NE release in a concentration-dependent manner. The IC50 values fo r inhibition of AMPA- or KA-induced [H-3]NE release by either antagoni st were not affected by the presence of cyclothiazide. Thus, cyclothia zide seems to interact at a site on the AMPA receptor complex which di ffers from either the glutamate recognition site or the 2,3-benzodiaze pine allosteric site.