6,7-Dinitroquinoxaline-2,3-dione and 6-nitro,7-cyanoquinoxaline-2,3-dione antagonize responses mediated by N-methyl-D-aspartate and NMDA-associated glycine recognition sites in vivo: measurements of cerebellar cyclic-GMP.
Direct intracerebellar administration of quisqualate resulted in marked increases in levels of cGMP in the cerebellum of the mouse, with a Hill number of 2.0. Quinoxalinediones, DNQX (6,7-dinitroquinoxaline-2,3-dione) and CNQX (6-nitro,7-cyanoquinoxaline-2,3-dione) attenuated the quisqualate-induced response. 6,7-Dinitroquinoxaline-2,3-dione also attenuated the D-serine-induced increases in levels of cGMP in a competitive manner. Intracerebellar injection of DNQX also antagonized the response to parenterally-administered harmaline. Similar results were also obtained with CNQX. These results indicate that these quinoxalinediones can attenuate the responses, mediated through the NMDA-associated glycine recognition sites, as well as the NMDA receptor complex. However, the glycine antagonist HA-966 (3-amino-1-hydroxypyrrolidone-2), at doses which completely reversed the increases induced by D-serine, failed to alter the response to quisqualate, indicating a lack of effect of glycine antagonists on quisqualate-mediated synaptic events. These results further support the interaction of the quinoxalinediones, DNQX and CNQX, with the NMDA receptor complex as established in receptor binding and electrophysiological studies.
Rao
T S
TS
G. D. Searle & Co., Monsanto Company, St Louis, Missouri 63198.
Cler
J A
JA
Mick
S J
SJ
Emmett
M R
MR
Iyengar
S
S
Wood
P L
PL
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism; D006246:Harmaline / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D016318:Quisqualic Acid / Q000494:pharmacology*; D012694:Serine / Q000494:pharmacology
D011760:Pyrrolidinones; D011810:Quinoxalines; D012694:Serine; C056723:FG 9041; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016318:Quisqualic Acid; D006246:Harmaline; D000242:Cyclic AMP; C001369:1-hydroxy-3-amino-2-pyrrolidone; D005998:Glycine