Correlation of vacuous chewing movements with morphological changes in rats following 1-year treatment with haloperidol

Abstract

Long-term treatment with the typical antipsychotic drug, haloperidol, can lead to a sometimes irreversible motor disorder, tardive dyskinesia (TD). It has been hypothesized that increased release of glutamate due to prolonged neuroleptic drug treatment may result in an excitotoxic lesion in specific neuronal populations within the basal ganglia, leading to TD. We reported that treatment with haloperidol for 1 month results in an increase in the mean percentage of striatal asymmetric synapses containing a perforated postsynaptic density (PSD) and that these synapses are glutamatergic. Using quantitative immunocytochemistry, we found that depending on how long the animals had been off haloperidol following subchronic (30 d) treatment, there was either a decrease (1 day off) or increase (3-4 days off) in the density of glutamate immunolabeling within the presynaptic terminals of synapses with perforated PSDs. Using a rat model for TD, animals in the current study were treated 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 between glutamate function, as measured by changes in synapses with perforated PSDs and the density of nerve terminal glutamate immunoreactivity, 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 perforated PSDs in both haloperidol-treated groups compared to vehicle-treated rats. There was a small but significant increase in the density of glutamate immunolabeling within striatal nerve terminals of the high VCM group compared to the low VCM group. There was, however, no difference in the density of glutamate immunolabeling between the high VCM group compared to the vehicle-treated animals. One reason for this lack of difference was partially due to a significant increase in nerve terminal area within the high VCM group compared to either the low VCM- or vehicle-treated groups. The larger nerve terminal size in the high VCM group may be due to a small but sustained increase in glutamate neurotransmitter release with the ability of the terminal to maintain its supply of glutamate, while the terminals in the low VCM group showed evidence of glutamate depletion. This finding would be consistent with the hypothesis that increased glutamatergic activity may be associated with TD.

Enhancement of N-methyl-D-aspartate (NMDA) immunoreactivity in residual dendritic spines in the caudate-putamen nucleus after chronic haloperidol administration

“…Our results confirm and extend earlier electron microscopic studies showing that chronic haloperidol treatment produces a decrease in the density of total dendritic spines accompanied by a corresponding decrease in axo-spinous asymmetric synapses and an increase in perforated synapses (Meshul and Casey, 1989;Meshul et al, , 1996aMeshul and Tan, 1994;Roberts et al, 1995;Kelley et al, 1997). In contrast, as compared to controls, we have shown a marked increase per unit area and volume of NMDAR1-labeled spines in the dorsolateral CPN using a modified disector method.…”

“…In addition, we examined serial as well as single sections of tissue, since the numbers of labeled profiles that appear in one section are directly related to several factors, including amount and subcellular distribution of immunoreactivity, as well as shape and size of individual profiles (West, 1993;Coggeshall and Lekan, 1996). The inclusion of data from single as well as serial sections permits more direct comparisons with earlier studies of haloperidol-induced morphological changes, most of which used only single sections (Meshul et al, , 1996aMeshul and Tan, 1994;Roberts et al, 1995). The use of the disector provides additional information in all quantitative studies (Coggeshall and Lekan, 1996), but proved to be essential in the present study.…”

“…These include: 1) an increase in the number of perforated axospinous synapses associated with the presence of vacuous chewing movements (Meshul et al, , 1996aMeshul and Tan, 1994); and 2) an increase in the total number of synapses (Uranova et al, 1991;Kerns et al, 1992), most of which are on dendritic spines. These structural modifications suggest that haloperidol produces a synaptic reorganization involving changes mainly in dendritic spines.…”

Changes in the pattern of brain-derived neurotrophic factor immunoreactivity in the rat brain after acute and subchronic haloperidol treatment

“…Neuroleptic drugs may exert their effects by altering neuronal structure. Many studies show that chronic treatment of experimental animals is associated with synaptic and dendritic changes in midbrain, prefrontal, neostriatal, and accumbal neurons, changes that have been linked both to the efficacious and motor side effects of these drugs (Benes et al, 1983(Benes et al, , 1985Meredith et al, 1997;Meshul et al, 1996;Roberts et al, 1995;Vincent et al, 1994).…”

Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study

“…Ultrastructural studies of APD effects in the striatum primarily focus on the dorsal striatum, where chronic (6 months or longer) haloperidol treatment results in reduced asymmetric synapse density 85,86 and reduced spine number. 87 Other studies of APD treatment have reported an increased percentage of perforated synapses in the caudate with no change in total number, and no differences present in the NAcc.…”