INHIBITION OF N-METHYL-D-ASPARTATE GLUTAMATE-RECEPTOR SUBUNIT EXPRESSION BY ANTISENSE OLIGONUCLEOTIDES REVEALS THEIR ROLE IN STRIATAL MOTORREGULATION

N-methyl-D-aspartate (NMDA) glutamate receptors have an established ro le in the regulation of motor behavior by the basal ganglia. Recent st udies have revealed that NMDA receptors are heteromeric assemblies of structurally related subunits from two families: NMDAR1, which is requ ired for channel activity, and NMDAR2A-D, which modulate the propertie s of the channels. In the rat, the NMDA receptor subunits exhibit anat omically restricted patterns of expression, so that each component of the basal ganglia has a distinct NMDA receptor subunit mRNA phenotype. We have used in vivo intrastriatal injection of synthetic antisense o ligodeoxynucleotides (ODNs) to examine the roles of particular NMDA re ceptor subunits in the regulation of motor behavior in rats. Injection of 15 nmol of a 20-mer ODN targeted to the NMDAR1 subunit induced spo ntaneous ipsilateral rotation. Smaller doses of NMDAR1 antisense ODN d id nor lead to spontaneous rotation, but prominent ipsilateral rotatio n was observed after systemic administration of D-amphetamine. An anti sense ODN to NMDAR2A was also effective in eliciting amphetamine-induc ible rotation, although the magnitude of the effect was less than that seen with NMDAR1, whereas ODNs targeted to NMDAR2B, NMDAR2C and an NM DAR1 sense strand ODN had no effect on behavior. In situ hybridization demonstrated that injection of the NMDAR1, NMDAR2A or NMDAR2B antisen se ODNs produced specific reductions in target mRNA signal intensity i n the injected striatum. After NMDAR1 antisense ODN injection, striata l binding of H-3-glutamate to NMDA sites was not altered, although str ychnine-insensitive H-3-glycine binding sites exhibited a small but si gnificant reduction. These observations suggest that NMDA receptor com plexes containing NMDAR1 and, to a lesser extent, NMDAR2A subunits pla y particularly important roles in the regulation of motor behavior by neostriatal neurons.