In vitro and in vivo characterization of the NMDA receptor-linked strychnine-insensitive glycine site

Abstract

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.