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 agonists, including AMPA and glutamate, has been shown to result in a rapid desensitization of the receptor. This desensitization is profoundly inhibited by the benzothiadiazide diuretic, cyclothiazide. We previously reported that cyclothiazide potentiates AMPA-induced [3H]norepinephrine ([3H]NE) release from rat hippocampal slices. We used this system to investigate the possible interaction of cyclothiazide with various AMPA receptor antagonists, including the competitive antagonist LY293558 and the 2,3-benzodiazepine noncompetitive antagonist GYKI 53655. Cyclothiazide significantly potentiated both AMPA- and KA-induced [3H]NE release from slices of the rat hippocampus. LY293558 and GYKI 53655 inhibited the potentiated and nonpotentiated AMPA- and KA-induced [3H]NE release in a concentration-dependent manner. The IC50 values for inhibition of AMPA- or KA-induced [3H]NE release by either antagonist were not affected by the presence of cyclothiazide. Thus, cyclothiazide seems to interact at a site on the AMPA receptor complex which differs from either the glutamate recognition site or the 2,3-benzodiazepine allosteric site.
Desai
M A
MA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Burnett
J P
JP
Ornstein
P L
PL
Schoepp
D D
DD
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001581:Benzothiadiazines / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D001581:Benzothiadiazines; D007546:Isoquinolines; D018091:Receptors, AMPA; D013777:Tetrazoles; D001569:Benzodiazepines; C079692:GYKI 53655; C082309:tezampanel; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C004639:cyclothiazide; D007608:Kainic Acid; D009638:Norepinephrine