Effects of new non-N-methyl-D-aspartate antagonists on synaptic transmission in the in vitro rat hippocampus

Abstract

1. The effects of new, potent non-N-methyl-D-aspartate (NMDA) receptor antagonists, 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), have been examined using intra- and extracellular recordings in the hippocampal slice preparation. In terms of potency and selectivity, the action of the two blockers was similar and CNQX was used in most experiments. 2. CNQX reduced the responses to ionophoretic applications of the non-NMDA agonists kainate (KAI) and quisqualate (QUIS) with IC50 values of 1.2 and 4.8 microM, respectively. In Mg2+-free solutions responses to NMDA were generally not affected by concentrations of CNQX up to 25 microM. 3. The action of CNQX was only slowly and poorly reversible on washing. Responses to QUIS and KAI were also reversibly reduced by ionophoretic application of CNQX. 4. CNQX blocked the evoked EPSP in CA1 and CA3 neurones with an IC50 of around 2 microM, which is similar to the IC50 for responses to KAI. CNQX was without effect on the passive membrane properties, the afferent volley and paired pulse potentiation. 5. In the presence of CNQX (greater than 5 microM) a small EPSP remained which was largest in CA1 neurones. It was blocked by low concentrations of the NMDA receptor antagonist (+/-)-2-amino-5-phosphonovaleric acid (APV), was markedly enhanced on removing Mg2+ ions from the bathing medium and, in voltage-clamp experiments, showed a potential dependence which is characteristic of the NMDA ionophore. 6. The latency of the APV-sensitive EPSP in CA1 was the same as the CNQX-sensitive EPSP, indicating that NMDA receptors participate in monosynaptic excitation. 7. Feedback and feed-forward inhibition in both area CA1 and CA3 were sensitive to CNQX. There seemed to be two components of the inhibition, both of which appear to be GABAergic since they could be blocked by picrotoxin (PTX), but only one of which was blocked by CNQX. The CNQX-resistant IPSP was not affected by APV. 8. In conclusion, quinoxalinediones have been used to demonstrate that non-NMDA receptors mediate the majority of the EPSP. Additionally, a component of the EPSP in CA1 is mediated by NMDA receptors and is manifested at resting membrane potentials and in the presence of Mg2+.