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Selective Potentiation of DNA Binding Activities of Both Activator Protein 1 and Cyclic AMP Response Element Binding Protein Through In Vivo Activation of N-Methyl-d-Aspartate Receptor Complex in Mouse Brain


Address correspondence and reprint requests to Dr. Y. Yoneda at the Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-01, Japan.


Abstract: DNA binding activities of several transcription factors were evaluated in nuclear extracts from brains of mice that were injected intracerebroventricularly with N-methyl-d-aspartic acid (NMDA) using gel-shift assays. An injection of saline transiently increased binding of both probes for activator protein 1 (AP1) and cyclic AMP response element binding protein (CREB) 30 min after the injection, and NMDA was effective in inducing a more potent increment of binding of both probes 1–5 h after the injection than did saline. However, no significant alterations were found in binding of probes for other transcription factors tested up to 4 h following the injection of NMDA. The potentiation by NMDA was prevented in a dose-dependent manner by administration of the non-competitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, the NMDA antagonist d,l-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid, and the glycine antagonist 5,7-dichlorokynurenic acid, whereas administration of the proposed polyamine antagonist ifenprodil was rather ineffective in protecting against the potentiation by NMDA. These results support the proposal that an intracerebroventricular injection of NMDA may selectively potentiate DNA binding activities of both AP1 and CREB through activation of the NMDA receptor complex in mouse brain.