Uncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptors alter the mRNA expression of proteins associated with the NMDA receptor complex.
N-methyl-D-aspartate (NMDA) receptor function appears to be under complex control during physiological and pharmacological states. We have investigated the effects of acute administration of uncompetitive NMDA receptor antagonists on mRNA levels of NMDA receptor subunits and on molecules known to cluster or phosphorylate the receptor utilizing in situ hybridization on rat brain sections. A high dose (5 mg/kg; 4 hr) of dizocilpine (MK-801) decreased mRNA levels of NMDA receptor subunits NR2C and NR2B in the entorhinal and parietal cortices, respectively. MK-801 increased mRNA levels of synapse-associated protein-90/postsynaptic density-95 (SAP90/PSD-95) and a gamma-isoform of protein kinase C (PKCgamma) in cortical regions. Synapse-associated protein-97 (SAP97) mRNA levels were increased in the entorhinal cortex layer III after MK-801 or after relatively high doses of other uncompetitive NMDA receptor antagonists: phencyclidine (15 mg/kg; 6 hr) and memantine (50 mg/kg; 6 hr). Memantine also increased SAP97 mRNA expression in other cortical regions, but this effect was not observed with MK-801 or phencyclidine. NMDA receptor uncompetitive antagonists alter the expression of multiple receptor components and such events may ultimately play a role in adaptation or toxic responses.
Lindén
A M
AM
A. I. Virtanen Institute, University of Kuopio, Finland.
Väsänen
J
J
Storvik
M
M
Lakso
M
M
Korpi
E R
ER
Wong
G
G
Castrén
E
E
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D015536:Down-Regulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics; D000074407:SAP90-PSD95 Associated Proteins
D048868:Adaptor Proteins, Signal Transducing; C501119:Dlg1 protein, rat; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D000074407:SAP90-PSD95 Associated Proteins; D016291:Dizocilpine Maleate; C087857:protein kinase C gamma; D011493:Protein Kinase C; D003024:Clozapine; D006220:Haloperidol