N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors regulating hippocampal norepinephrine release. III. Changes in...

N-methyl-D-aspartic acid (NMDA) and non-NMDA ionotropic receptors mediating increase of norepinephrine (NE) release coexist on NE rat hippocampus axon terminals. Activation of non-NMDA receptors permits activation of NMDA receptors also in presence of Mg++ ions and induces important changes in the NMDA receptor recognition site and in its intrinsic ion channel. We have now studied the effects of this receptor-receptor interaction on the glycine site of the NMDA receptor by using two antagonists, 7-chloro-kynurenic acid and (+-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966). Both the [3H]NE releases induced from rat hippocampus synaptosomes by NMDA (no Mg++ added) and by NMDA+quisqualic acid (QA), in the presence of 1.2 mM Mg++, were prevented by 7-chloro-kynurenic acid with almost identical potency (IC50 values: 0.19 and 0.39 microM, respectively). In contrast, HA-966, up to 1000 microM, was ineffective toward NMDA (no Mg++), but it blocked the effect of NMDA + QA in presence of Mg++ (IC50 = 1.1 microM). HA-966 also antagonized NMDA + QA in Mg(++)-free medium. Thus coactivation of non-NMDA and NMDA receptors seems to permit the antagonistic activity of HA-966. In the presence of Mg++, L-glutamic acid (L-Glu) enhanced [3H]NE release. The sensitivity of the L-Glu effect to various antagonists was similar to that of the effect of NMDA + QA, indicating that the NMDA receptor complex activated either by NMDA + QA or by the physiological transmitter L-Glu in presence of Mg++ ions undergoes dramatic conformational changes at the recognition site, at the ion channel as well as at the glycine site.