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(Accepted April 19, 2001)
The effects of continuous infusion of NMDA receptor antagonist MK-801 on the modulation of NMDA receptor subunits NR1, NR2A, NR2B, and NR2C were investigated by using in situ hybridization study. Differential assembly of NMDA receptor subunits determines their functional characteristics. Continuous intracerebroventricular (i.c.v.) infusion with MK-801 (1 pmol/10 ml/h) for 7 days resulted in significant modulations in the NR1, NR2A, and NR2B mRNA levels without producing stereotypic motor syndromes. The levels of NR1 mRNA were significantly increased (9-20%) in the cerebral cortex, striatum, septum, and CA1 of hippocampus in MK-801-infused rats. The levels of NR2A mRNA were significantly decreased (11-16%) in the CA3 and dentate gyrus of hippocampus in MK-801-infused rats. In contrast to NR2A, NR2B subunit mRNA levels were increased (10-14%) in the cerebral cortex, caudate putamen, and thalamus. However, no changes of NR2C subunits in cerebellar granule layer were observed. Using quantitative ligand autoradiography, the binding of NMDA receptor ligand [3H]MK-801 was increased (12-25%) significantly in almost all brain regions except in the thalamus and cerebellum after 7 days infusion with MK-801. These results suggest that region-specific changes of NMDA receptor subunit mRNA and [3H]MK-801 binding are involved in the MK-801-infused adult rats.
KEY WORDS: NMDA receptor; MK-801; in situ hybridization; autoradiography; osmotic pump.
INTRODUCTION
Glutamate is the major rapidly acting excitatory neurotransmitter in the mammalian central nervous system and is in high concentration (approximately 100 mM) in glutamatergic synaptic vesicles (1). Abnormal activation of glutamate receptors can be neurotoxic and may be involved in the pathogenesis of a number of neurological disorders (2). The glutamate receptors can be classified into two subgroups, termed the ionotropic and metabotropic receptors. Ionotropic glutamate receptors are ligand-gated ion channels and are further divided into two major subtypes: those that are responsive to the selective agonist N-methyl-Daspartate (NMDA) and those that respond to either a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or kainate. Of the ionotropic glutamate receptors, the NMDA subtype has been the most extensively characterized. The NMDA receptor is susceptible to blockade by drugs acting at several different sites on the receptor-channel complex. Antagonists may interact with the recognition sites for glutamate, glycine, and an ion channel permeable to Ca21 and Na1. A common characteristic of these various NMDA antagonists is that they have...