Blockade of NMDA receptors by MK‐801 reverses the changes in striatal glutamate immunolabeling in 6‐OHDA‐lesioned rats

Abstract

A lesion of the dopamine (DA)-containing nigrostriatal pathway with 6-hydroxydopamine (6-OHDA) results in an increase in the density of nerve terminal glutamate immunolabeling and in the mean percentage of asymmetrical synapses containing a discontinuous postsynaptic density [Meshul et al. (1999) Neuroscience 88:1-16]. Similar alterations in striatal glutamate synapses have been reported following blockade of striatal DA D-2 receptors with subchronic haloperidol treatment [Meshul et al. (1994) Brain Res 648:181-195]. The haloperidol-induced change in glutamate synapses was blocked by coadministration of the N-methyl-D-aspartate (NMDA) noncompetitive receptor antagonist MK-801. In order to determine if blockade of NMDA receptors could alter the density of nerve terminal glutamate immunolabeling following a 6-OHDA lesion of the nigrostriatal pathway, MK-801 was administered to lesioned animals for 14 days. In addition, the number of apomorphine-induced contralateral rotations was determined prior to and following the administration of MK-801. MK-801 administration reversed the increase in the density of nerve terminal glutamate immunolabeling due to a 6-OHDA lesion. There was a small but significant decrease in the number of apomorphine-induced contralateral rotations following administration of MK-801 compared to the number of rotations prior to treatment with the NMDA antagonist. These results demonstrate that blockade of postsynaptic NMDA receptors affects the density of presynaptic glutamate immunolabeling and that this change in nerve terminal glutamate density is associated with a decreased behavioral response to direct DA receptor stimulation. Whether the effect of MK-801 is directly on the striatum or acts through other excitatory pathways of the basal ganglia remains unclear.