EVIDENCE FOR FUNCTIONAL NATIVE NMDA RECEPTORS ACTIVATED BY GLYCINE ORD-SERINE ALONE IN THE ABSENCE OF GLUTAMATERGIC COAGONIST

In this study we have examined the effects of N-methyl-D-aspartate (NM DA) receptor activation on the release of cholecystokinin and somatost atin from rat neocortical nerve endings. The release of cholecystokini n-like immunoreactivity (CCK-LI) and of somatostatin-like immunoreacti vity (SRIF-LI) elicited by 12 mM K+ from superfused synaptosomes, but not the spontaneous release, was increased by NMDA in a concentration- dependent manner. The effects of NMDA could be prevented by antagonist s selective for the glutamate recognition site, the receptor channel a nd the glycine site of the NMDA receptor. In the absence of NMDA, glyc ine increased on its own and in a concentration-dependent manner the d epolarization-evoked release of both CCK-LI and SRIF-LI. This effect o f glycine was strychnine-insensitive and could be mimicked by D-serine , a stereoselective agonist at the NMDA receptor glycine site. Antagon ists selective for the glycine site or for the NMDA receptor channel p revented the effects of glycine/D-serine; these effects were, however, insensitive to blockade of the glutamate recognition site of the NMDA receptor, suggesting that glutamate released from synaptosomes or pre sent as contaminant was not involved. The neuropeptide release elicite d by D-serine was strongly inhibited by ifenprodil (0.3 mu M) and by Z n2+ ions (50 nM), selective ligands at the NR2B and NR2A subunits of N MDA receptors, respectively. It is concluded that nerve terminals of C CK- and SRIF-releasing neurons possess non-conventional NMDA receptors whose channels can be operated by glycine or D-serine without apparen t activation of the glutamatergic coagonist site. These receptors may display the triple subunit combination NR1/NR2A/NR2B.