CORRELATION OF VACUOUS CHEWING MOVEMENTS WITH MORPHOLOGICAL-CHANGES IN RATS FOLLOWING 1-YEAR TREATMENT WITH HALOPERIDOL

Long-term treatment with the typical antipsychotic drug, haloperidol, can lead to a sometimes irreversible motor disorder, tardive dyskinesi a (TD). It has been hypothesized that increased release of glutamate d ue to prolonged neuroleptic drug treatment may result in an excitotoxi c lesion in specific neuronal populations within the basal ganglia, le ading to TD. We reported that treatment with haloperidol for 1 month r esults in an increase in the mean percentage of striatal asymmetric sy napses containing a perforated postsynaptic density (PSD) and that the se synapses are glutamatergic. Using quantitative immunocytochemistry, we found that depending on how long the animals had been off haloperi dol following subchronic (30d) treatment. there was either a decrease (1 day off) or increase (3-4 days off) in the density of glutamate imm unolabeling within the presynaptic terminals of synapses with perforat ed PSDs. Using a rat model for TD, animals in the current study were t reated for 1 year with haloperidol and spontaneous oral dyskinesias (i .e. vacuous chewing movements, VCMs) were recorded, In these long-term treated animals we wanted to determine if there was a correlation bet ween glutamate function, as measured by changes in synapses with perfo rated PSDs and the density of nerve terminal glutamate immunoreactivit y, and VCM behavior. In drug treated rats which demonstrated either a high or low rate of VCMs, there was a significant increase in the mean percentage of asymmetric synapses in the dorsolateral striatum with p erforated PSDs in both haloperidol-treated groups compared to vehicle- treated rats. There was a small but significant increase in the densit y of glutamate immunolabeling within striatal nerve terminals of the h igh VCM group compared to the low VCM group, There was, however, no di fference in the density of glutamate immunolabeling between the high V CM group compared to the vehicle-treated animals. One reason for this lack of difference was partially due to a significant increase in nerv e terminal area within the high VCM group compared to either the low V CM- or vehicle-treated groups. The larger nerve terminal size in the h igh VCM group may be due to a small but sustained increase in glutamat e neurotransmitter release with the ability of the terminal to maintai n its supply of glutamate, while the terminals in the low VCM group sh owed evidence of glutamate depletion. This finding would be consistent with the hypothesis that increased glutamatergic activity may be asso ciated with TD.