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

A lesion of the dopamine (DA)-containing nigrostriatal pathway with 6-hydro xydopamine (6-OHDA) results in an increase in the density of nerve terminal glutamate immunolabeling and in the mean percentage of asymmetrical synaps es containing a discontinuous postsynaptic density [Meshul et al. (1999) Ne uroscience 88:1-16]. Similar alterations in striatal glutamate synapses hav e been reported following blockade of striatal DA D-2 receptors with subchr onic haloperidol treatment [Meshul et al. (1994) Brain Res 648:181-195]. Th e haloperidol-induced change in glutamate synapses was blocked by coadminis tration of the N-methyl-D-aspartate (NMDA) noncompetitive receptor antagoni st MK-801. In order to determine if blockade of NMDA receptors could alter the density of nerve terminal glutamate immunolabeling following a 6-OHDA l esion of the nigrostriatal pathway, MK-801 was administered to lesioned ani mals for 14 days. In addition, the number of apomorphine-induced contralate ral rotations was determined prior to and following the administration of M K-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 contralatera l rotations following administration of MK-801 compared to the number of ro tations prior to treatment with the NMDA antagonist. These results demonstr ate that blockade of postsynaptic NMDA receptors affects the density of pre synaptic glutamate immunolabeling and that this change in nerve terminal gl utamate density is associated with a decreased behavioral response to direc t DA receptor stimulation. Whether the effect of MK-801 is directly on the striatum or acts through other excitatory pathways of the basal ganglia rem ains unclear. Synapse 42:54-61, 2001. (C) 2001 Wiley-Liss, Inc.