Induction of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) expression in rat brain by uncompetitive N-methyl-D-aspartate receptor antagonists

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 re gulatable transcription factors play a role in the neurochemical actions of agents acting through NMDA receptors, the effects of the acute administrat ion 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 se ctions revealed that ICER mRNA expression was significantly increased by un competitive NMDA receptor antagonists (MK-801, phencyclidine, ketamine, mem antine) but not by the competitive antagonist CPP [(+/-)-3-(2-carboxypipera zin-4-yl)-propyl-1-phosphonic acid] or other psychotropic agents (clozapine , haloperidol, desipramine). Major brain regions where ICER transcripts wer e increased were the hippocampus, parietal cortex layers IV and VI, tempora l cortex, cingulate cortex, thalamus, and granule cell layer of the olfacto ry bulb. Northern and Western blot analyses indicated that CREM mRNA and pr otein, respectively, were also increased after MK-801 treatment, but ICER i soforms predominate during both basal and induced conditions. MK-801 also t ransiently increased the binding of proteins to cAMP response element, whic h was supershifted by anti-CREM antibody, indicating that increased mRNA an d protein levels have functional consequences on gene transcription. These results provide evidence for the involvement of CREM and ICER family transc ription factors in the pharmacologic effects of uncompetitive NMDA receptor antagonists.