Abstract
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.
Footnotes
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Send reprint requests to: Garry Wong, Ph.D., A. I. Virtanen Institute, University of Kuopio, PL 1627, Kuopio 70211, Finland. E-mail:garry.wong{at}uku.fi
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↵1 This study was supported by the Sigrid Juselius Foundation, J. and R. Ahokas Foundation, Academy of Finland, and the Finnish Technology Research Center (TEKES). G.W. was a recipient of a Junior Research Fellow Grant from the Academy of Finland.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- BDNF
- brain-derived neurotrophic factor
- CPP
- (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid
- CRE
- cAMP response element
- CREB
- cAMP response element-binding protein
- CREM
- cAMP response element modulator
- ICER
- inducible cAMP early repressor
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- PIPES
- 1,4-piperazinediethanesulfonic acid
- SSC
- standard sodium citrate
- DTT
- dithiothreitol
- bp
- base pair(s)
- Received January 3, 2000.
- Accepted March 9, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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