Augmentation by glycine and blockade by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) of responses to excitatory amino acids in slices of rat neocortex.

Responses of neocortical pyramidal cells to excitatory amino acids were recorded intracellularly. Agonists and antagonists were applied electrophoretically from a separate multibarrel pipette and care taken to ensure that the pipette was positioned to evoke optimal responses to N-methyl-D-aspartate (NMDA), or homocysteic acid, before control responses were recorded. Responses to NMDA, but not those to alpha-amino-3-hydroxy-5-methyl-4-isoxazdepropionic acid (AMPA) or quisqualate, were enhanced when glycine was co-applied. Responses to AMPA, quisqualate and NMDA were reduced by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) applied either electrophoretically, or in the bathing medium, with responses to quisqualate being the least and those to AMPA being the most sensitive to CNQX. The blockade of NMDA responses by CNQX was selectively reversed by additional glycine confirming that CNQX blocks NMDA receptor-channel complexes at the glycine, rather than at the NMDA site. Under control conditions, responses to glutamate resembled responses to quisqualate, and were relatively insensitive to CNQX, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid and 2-amino-5-phosphonovalerate, while responses to homocysteic acid resembled responses to NMDA and were blocked by these antagonists. This suggested that homocysteic acid acted at NMDA receptors, while glutamate acted primarily at non-NMDA receptors. However, responses to both glutamate and homocysteic acid were augmented by additional glycine when these transmitter candidates were applied close to a "hot spot" for NMDA receptor activation. The glycine enhancement of responses to glutamate was sensitive to NMDA antagonists, indicating that glutamate can activate NMDA receptors in an intact preparation if glycine levels are high enough.