Haloperidol reverses the changes in striatal glutamatergic immunolabeling following a 6-OHDA lesion.

We reported previously that 3 months following a unilateral lesion of the nigrostriatal pathway with 6-hydroxydopamine (6-OHDA), there was a decrease in the extracellular level of striatal glutamate as determined by in vivo microdialysis. This resulted in an accumulation or increase in the density of nerve terminal glutamate immunolabeling (Meshul et al., 1999). We also reported on blockade of dopamine D-2 receptors with haloperidol resulting in ultrastructural changes within the striatum consistent with increased functioning of the glutamatergic corticostriatal pathway (Meshul and Tan 1994). We hypothesized that administration of haloperidol to 6-OHDA-lesioned rats may be capable of activating the corticostriatal pathway and thereby counteracting the effects of the unilateral nigrostriatal lesion. Striatal glutamatergic function was evaluated using electron microscopy and quantitative glutamate immunocytochemistry. Starting 1 month after a unilateral lesion of the nigrostriatal pathway with 6-OHDA, haloperidol (0.5 mg/kg/d) was administered for the next 2 months. Within the dorsolateral caudate nucleus, the main area of innervation from the motor cortex, haloperidol blocked the 6-OHDA-induced increase in the density of nerve terminal glutamate immunolabeling. Within all three experimental groups (6-OHDA, haloperidol, 6-OHDA/haloperidol) there was an increase in the mean percentage of striatal asymmetrical synapses containing a perforated postsynaptic density. In addition, haloperidol treatment resulted in a reduction in the number of apomorphine-induced contralateral rotations in unilaterally 6-OHDA lesioned rats. The data suggests that the decrease in striatal glutamatergic function 3 months following a unilateral 6-OHDA lesion can be reversed by daily haloperidol treatment. This finding is discussed in terms of current therapy for Parkinson's disease. Synapse 36:129-142, 2000. Published 2000 Wiley-Liss, Inc.