D-2 DOPAMINE-RECEPTOR MESSENGER-RNA IS ALTERED TO A GREATER EXTENT BY BLOCKADE OF GLUTAMATE RECEPTORS THAN BY BLOCKADE OF DOPAMINE-RECEPTORS

To study further the molecular mechanisms by which glutamate and dopamine interact to regulate the functions of the basal ganglia, the effects of persistently inhibiting dopamine receptors and glutamate N-methyl-D-aspartate receptors on the density of D-1 and D-2 dopamine receptors and on the level of their transcripts were examined in mouse brain. To block dopamine receptors, mice were treated with N-ethoxycarbonyr-2-ethoxy-1,2-dihydroquinoline once daily for two and six days, or were treated with fluphenazine-N-mustard once daily for five days. To block N-methyl-D-aspartate receptors, mice were treated with dizocilpine by continuous infusion with osmotic mini-pumps for two and six days. The density of D-1 and D-2 dopamine receptors was measured by receptor autoradiography, and the lever of D-1 and D-2 dopamine receptor messenger RNA was measured by in situ hybridization histochemistry. The results showed that N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline blocked about 90% of both D-1 and D-2 dopamine receptors, but had no significant effect on the lever of either D-1 or D-2 dopamine receptor messenger RNA. Fluphenazine-N-mustard, which was as effective as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in blocking D-2 dopamine receptors but had little effect on D-1 dopamine receptors, also had no significant effect on the level of D-1 and D-2 dopamine receptor messenger RNAs. By contrast, continuously infusing dizocilpine significantly decreased the levels of D-1 dopamine receptor messenger RNA in striatum, nucleus accumbens and olfactory tubercle. Dizocilpine also caused small decreases in the density of D-2 dopamine receptors, but only in posterior striatum was this decrease statistically significant. Dizocilpine slightly and transiently decreased the levels of D-1 dopamine receptor messenger RNA in striatum but had no significant effect on the density of D-1 dopamine receptors in any region examined. This study demonstrates that persistent blockade of D-1, and D-2 dopamine receptors has relatively little effect on the levels of D-1 and D-2 dopamine receptor messenger RNA, but that blockade of N-methyl-D-aspartate receptors produces a rapid and profound decrease in the levels of D-2 dopamine receptor messenger RNA and a smaller decrease in the density of D-2 dopamine receptors. These results suggest that N-methyl-D-aspartate receptors play an important role in the expression of D-2 dopamine receptors in basal ganglia.