Uncompetitive Antagonists of the N-Methyl-D-aspartate (NMDA) Receptors Alter the mRNA Expression of Proteins Associated with the NMDA Receptor Complex

Abstract

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.

Glutamate Receptor Subunits are Altered in Forebrain and Cerebellum in Rats Chronically Exposed to the NMDA Receptor Antagonist Phencyclidine

“…Our NR2B protein results are also consistent with neonatal changes seen in NR2B mRNA levels in the frontal cortex following chronic postnatal PCP exposure (Sircar et al, 1996). However, they do not reflect either the null change in parietal cortex or the prefrontal cortex decrease in NR2B mRNA following PCP treatment that has been reported previously (Linden et al, 2001;Oh et al, 2001). It is interesting to note that chronic PCP antagonism of the NMDA receptor under our experimental conditions produced minimal, insignificant changes in the NR2A subunit in either the frontal cortex, hippocampus or cerebellum.…”

“…Of the NR2 subunit proteins examined in the prefrontal cortex, NR2B and NR2C were similarly reduced and NR2D was significantly elevated following chronic PCP exposure. Reduced levels of NR2B and NR2C subunit proteins mirror the transcript findings by Linden et al (2001) for the parietal cortex treated with MK801. Our NR2B protein results are also consistent with neonatal changes seen in NR2B mRNA levels in the frontal cortex following chronic postnatal PCP exposure (Sircar et al, 1996).…”

“…They noted no change in NR2C message. In contrast, Linden et al (2001) demonstrated an MK801-associated decrease in both NR2B and NR2C mRNA in rat parietal cortex and no PCP-associated changes in any NR2 message. Al-Amin et al (2003) similarly found no alterations in NR2 subunit message from nucleus accumbens, striatum, cingulated, or piriform cortex with chronic MK801 treatment.…”

“…These behaviors typically manifest for 2-3 h following acute exposures, but persist for extended periods (412 h) with chronic dosaging (421 days). While others have reported changes in specific NMDA subunit gene transcripts following pharmacological antagonism of the NMDA receptor (Al-Amin et al, 2003;Linden et al, 2001;Oh et al, 2001;Wang et al, 1999;Wilson et al, 1998;Sircar et al, 1996), the regulation of NMDA and AMPA receptor proteins by chronic receptor antagonism has yet to be described. Examining the NMDA glutamate receptor at a level other than transcriptional control merits attention, given the plethora of post-transcriptional and post-translational modification events known to modulate receptor availability, complex assembly, subunit delivery, and membrane insertion.…”

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

“…As BDNF/TrkB signaling is a potent regulator for the expression of various PDZ protein (Jourdi et al 2001;Sato et al 2001), the impaired BDNF/TrkB signaling of schizophrenic patients might be responsible for the SAP97 protein decrease in the prefrontal cortex of schizophrenic patients. Interestingly, a major psychotomimetic drug, phencyclidine, acutely alters SAP97 gene expression, suggesting a potential link between psychotic symptoms and the PDZ protein SAP97 (Linden et al 2001). Accordingly, the impaired protein expression of SAP97 and GluR1 in the prefrontal cortex might be associated with the hypofunction of the prefrontal cortex in schizophrenic patients revealed by the above neurochemical studies as well as by neuroimaging studies (Weinberger et al 1986;Selemon et al 1995;Andreasen et al 1997;Duncan et al 1999;Bressan and Pilowsky 2000).…”