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 c ontrol during physiological and pharmacological states. We have investigate d the effects of acute administration of uncompetitive NMDA receptor antago nists on mRNA levels of NMDA receptor subunits and on molecules known to cl uster or phosphorylate the receptor utilizing in situ hybridization on rat brain sections. A high dose (5 mg/kg; 4 hr) of dizocilpine (MK-801) decreas ed mRNA levels of NMDA receptor subunits NR2C and NR2B in the entorhinal an d parietal cortices, respectively. MK-801 increased mRNA levels of synapse- associated protein-90/postsynaptic density-95 (SAP90/PSD-95) and a gamma -i soform of protein kinase C (PKC gamma) in cortical regions. Synapse-associa ted protein-97 (SAP97) mRNA levels were increased in the entorhinal cortex layer III after MK-801 or after relatively high doses of other uncompetitiv e NMDA receptor antagonists: phencyclidine (15 mg/kg: 6 hr) and memantine ( 50 mg/kg; 6 hr). Memantine also increased SAP97 mRNA expression in other co rtical regions, but this effect was not observed with MK-801 or phencyclidi ne. NMDA receptor uncompetitive antagonists alter the expression of multipl e receptor components and such events may ultimately play a role in adaptat ion or toxic responses.