In vitro and in vivo characterization of the NMDA receptor-linked strychnine-insensitive glycine site.
Modulation of the NMDA receptor by the strychnine-insensitive glycine site was studied both in vitro and in vivo. In vitro the glycinergic stimulation of [3H]MK801 binding was measured in three different rat forebrain membrane preparations. An increased association rate of [3H]MK801 in the presence of glycine was observed. The binding of the radioligand was also enhanced by D-serine, whereas L-serine was less potent. The concentration-effect curves were shifted to the right by the glycine antagonist 7-chlorokynurenic acid (7CKA). In vivo modulation of the N-methyl-D-aspartate (NMDA) receptor was studied using NMDA induced convulsions in 7 day old rats. The NMDA effect was blocked by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten,5,10-imine maleate (MK801) and D-(-)-2-amino-5-phosphono-pentanoic acid (AP5). The effect of a submaximal dose of NMDA was dose-dependently potentiated by 1-10 mg/kg D-serine, whereas higher doses of L-serine were needed to obtain a similar effect. 7CKA did not affect NMDA-induced convulsions but reduced the D-serine potentiation of NMDA responses. This study illustrates the ability of the strychnine-insensitive glycine site to modulate the NMDA receptor function both in vitro and in vivo.
Peeters
B W
BW
Department CNS Pharmacology, Organon International B.V., Oss Netherlands.
Vanderheyden
P M
PM
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D005998:Glycine / Q000502:physiology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism; D012694:Serine / Q000494:pharmacology; D013237:Stereoisomerism; D013331:Strychnine / Q000494:pharmacology*
D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; D013331:Strychnine; C057013:7-chlorokynurenic acid; D005998:Glycine