PT  - JOURNAL ARTICLE
AU  - Markus Storvik
AU  - Anni-Maija Lindén
AU  - Outi Kontkanen
AU  - Merja Lakso
AU  - Eero Castrén
AU  - Garry Wong
TI  - Induction of cAMP Response Element Modulator (CREM) and Inducible cAMP Early Repressor (ICER) Expression in Rat Brain by Uncompetitive<em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor Antagonists
DP  - 2000 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 52--60
VI  - 294
IP  - 1
4099  - http://jpet.aspetjournals.org/content/294/1/52.short
4100  - http://jpet.aspetjournals.org/content/294/1/52.full
SO  - J Pharmacol Exp Ther2000 Jul 01; 294
AB  - The N-methyl-d-aspartate (NMDA) subtype of glutamate receptor mediates fast excitatory neurotransmission, and agents that attenuate this function are neuroprotective, anesthetic, and psychotropic. To determine whether cAMP regulatable transcription factors play a role in the neurochemical actions of agents acting through NMDA receptors, the effects of the acute administration of uncompetitive and competitive antagonists on the expression of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) transcription factors were examined. In situ hybridization to rat brain sections revealed that ICER mRNA expression was significantly increased by uncompetitive NMDA receptor antagonists (MK-801, phencyclidine, ketamine, memantine) but not by the competitive antagonist CPP [(±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid] or other psychotropic agents (clozapine, haloperidol, desipramine). Major brain regions where ICER transcripts were increased were the hippocampus, parietal cortex layers IV and VI, temporal cortex, cingulate cortex, thalamus, and granule cell layer of the olfactory bulb. Northern and Western blot analyses indicated that CREM mRNA and protein, respectively, were also increased after MK-801 treatment, but ICER isoforms predominate during both basal and induced conditions. MK-801 also transiently increased the binding of proteins to cAMP response element, which was supershifted by anti-CREM antibody, indicating that increased mRNA and protein levels have functional consequences on gene transcription. These results provide evidence for the involvement of CREM and ICER family transcription factors in the pharmacologic effects of uncompetitive NMDA receptor antagonists. The American Society for Pharmacology and Experimental Therapeutics