Markus Storvik

Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists, such as dizocilpine (MK-801) and memantine, bind to the NMDA receptor channel, and block Ca influx. The increase in intracellular concentration of second messengers, such as Ca and cyclic adenosine monophosphate (cAMP), activate the transcription of certain genes. This process is controlled by cAMP response element binding protein (CREB), a transcription factor that can be activated by synaptic activity. The aim of the present study was to characterize alterations in the expression of transcription factors produced by NMDA receptor antagonists. Regulation of gene expression of CREB and its modulators, and glutamate receptor subunits were studied after MK-801 administration. In addition, the gene expression profiles in rat brains after MK801, with or without cocaine, were studied with DNA microand macro arrays. High, but transient induction of genes related to CREB, such as inducible cAMP early repressor (ICER) and other CREM-family transcripts, were found following uncompetitive NMDA antagonist treatment. These induced transcripts, alone or in heterodimers with other transcription factors, were found to bind CRE-elements in DNA. The uncompetitive NMDA antagonists are therefore capable of altering the transcription of genes expressed in neurons. The effect of the acute NMDA-antagonist MK-801 on the expression of glutamate receptor subunits was also determined and mGluR3, GluR3 and GluR4 were affected. Finally, two DNA microarray experiments were performed after treatment with acute MK-801, acute cocaine, or after a combination of MK-801 and cocaine. The expression of altered genes on parietal cortex, frontal cortex, and in nucleus accumbens was profiled. Although MK-801 did not prevent the alterations in gene expression caused by cocaine, a high number of transcription factors and signalling transduction genes were among the 850 candidate genes. In conclusion, these findings provide new information about the acute effects of uncompetitive NMDA on the regulation of gene transcription, which in turn leads to long-term changes in the brain. These findings should help to determine the baseline of how alterations in gene expression in brain develop during NMDA antagonist treatment. National Library of Medicine Classification: QU 26.5, QU 60, QV 76.5, QV 113, QZ 52 Medical Subject Headings: gene expression regulation; gene expression profiling; receptors, N-methyl-D-aspartate / antagonists & inhibitors; dizocilpine maleate; cocaine; DNA-binding protein, cyclic AMP-responsive; transcription factors; repressor proteins; oligonucleotide array sequence analysis; in situ hybridization; rats; brain; computational biology