Neuroleptic-induced Vacuous Chewing Movements Research Articles

Parallels between behavioral and neurochemical variability in the rat vacuous chewing movement model of tardive dyskinesia

The widely accepted rat vacuous chewing movement model for tardive dyskinesia could be more fully mined through greater focus on individual variability in vulnerability to this neuroleptic-induced behavior. We have examined parallels between behavioral and neurobiological variability within a cohort in order to evaluate the role that neurobiological factors might play in determining susceptibility to tardive dyskinesia. Inter-observer reliability and individual consistency across time, in both spontaneous and neuroleptic-induced vacuous chewing movements, were empirically demonstrated. While this behavior increased across 8 months of observation in both vehicle controls and haloperidol-treated rats, pre-treatment baselines were predictive of final levels across individuals only in the vehicle control group, not the haloperidol-treated group. Haloperidol-induced elevations in neostriatal D2 and GAD67 mRNA were not correlated with individual variability in haloperidol-induced vacuous chewing movements. Ambient noise during the observations was found to exacerbate chronic haloperidol-induced, but not spontaneous vacuous chewing movements. Significant correlations were found among the haloperidol-treated rats between nigral and tegmental GAD67 and tegmental α7 mRNA levels, measured by in situ hybridization histochemistry, and vacuous chewing movements, specifically in the noisy conditions. Variability in these secondary responses to primary striatal dopamine and GABA perturbations may play a role in determining vulnerability to vacuous chewing movements, and by analogy, tardive dyskinesia. Both the differential predictive value of baseline vacuous chewing movements and the differential effect of noise, between controls and haloperidol-treated rats, add to evidence that haloperidol-induced vacuous chewing movements are regulated, in part, by different mechanisms than those mediating spontaneous vacuous chewing movements.

Modulatory effect of neurosteroids in haloperidol-induced vacuous chewing movements and related behaviors

Tardive dyskinesia is a syndrome of abnormal and involuntary movements which occurs as a complication of long-term neuroleptic therapy especially classical neuroleptics such as haloperidol and chlorpromazine. Dysfunction of GABA receptor mediated inhibition, and increased glutamatergic neurotransmission has been implicated in the development of orofacial dyskinesia in rats and tardive dyskinesia in humans. Neurosteroids modulate both GABAergic as well as glutamatergic neurotransmission in various brain areas. The objective of the present study was to elucidate the role of various neurosteroids in neuroleptic-induced vacuous chewing movements and related behaviors in rats by using behavioral, biochemical, and neurochemical parameters. Animals chronically treated with haloperidol (1 mg/kg i.p.) for a period of 21 days exhibited marked increase in vacuous chewing movements, tongue protrusions, and facial jerkings as compared to vehicle-treated controls. It also resulted in increased superoxide anion levels and lipid peroxidation, whereas decreased levels of endogenous antioxidant enzymes (catalase and superoxide dismutase) in rat brain striatum homogenates. Neurochemical studies revealed that chronic administration of haloperidol resulted in significant decrease in the levels of dopamine, serotonin, and norepinephrine in rat brain striatum homogenates, whereas urine biogenic amines metabolite levels were increased. In a series of experiments, rats co-administered with allopregnanolone (0.5, 1, and 2 mg/kg i.p.) and progesterone (5, 10, and 20 mg/kg i.p.), both positive GABA-modulating [negative N-methyl-D-aspartate (NMDA)-modulating] neurosteroids prevented, whereas pregnenolone (0.5, 1, and 2 mg/kg i.p.) and dihydroxyepiandrosterone sulfate (0.5, 1, and 2 mg/kg i.p.) both negative GABA-modulating (positive NMDA-modulating) neurosteroids aggravated all the behavioral, biochemical, and neurochemical parameters. These results suggest that neurosteroids may play a significant role in the pathophysiology of vacuous chewing movements and related behaviors by virtue of their action on either the GABA or NMDA modulation. Furthermore, neurosteroids showing selectivity for positive GABA modulation and/or negative NMDA modulation may be particularly efficacious as novel therapeutic agents for the treatment of tardive dyskinesia and deserve further evaluation.

Effect of 5-HT 1A and 5-HT 2A/2C receptor modulation on neuroleptic-induced vacuous chewing movements

Tardive dyskinesia is a serious motor side effect of chronic neuroleptic therapy. Chronic treatment or rats with neuroleptics leads to the development of abnormal oral movements called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Atypical antipsychotics such as clozapine and rispiridone are associated with a lower incidence of extrapyramidal side effects and tardive dyskinesia. The present study was aimed to explore the role of 5-HT 1A, 5-HT 2A/2C receptors in the expression of neuroleptic-induced orofacial dyskinesia. In the present study rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to elicit vacuous chewing movements. The neuroleptic-induced vacuous chewing movements, viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5-min observation period. Acute treatment with 8-hydroxy-2-(di- n-propylamino) tetralin (8-OH-DPAT), a 5-HT 1A receptor agonist, dose-dependently (0.05, 0.1 and 0.2 mg/kg, i.p.) reduced the haloperidol-induced vacuous chewing movements and headshakes. Both acute and chronic administration of seganserin, ketanserin and ritanserin, 5-HT 2A/2C receptor antagonists, also reduced haloperidol-induced vacuous chewing movements in a dose-dependent (0.05, 0.1 and 0.2 mg/kg, i.p.) manner. In acute studies a higher dose of ritanserin (1 mg/kg) but not ketanserin (1 mg/kg) increased vacuous chewing movements, whereas a higher dose of seganserin (1 mg/kg) did not have any effect on vacuous chewing movements. All the drugs reduced haloperidol-induced headshakes in a dose-dependent fashion. These findings indicate that the serotonergic system, and particularly 5-HT 1A and 5-HT 2A/2C receptors, may be involved in haloperidol-induced orofacial dyskinesia, and that 5-HT receptors may provide novel targets for the development of drugs that can be used to reverse or prevent the extrapyramidal side effects associated with long-term antipsychotic treatment.

Excitatory mechanisms in neuroleptic-induced vacuous chewing movements (VCMs): possible involvement of calcium and nitric oxide

Tardive dyskinesia (TD) is a serious motor side-effect of chronic neuroleptic therapy. Chronic treatment with neuroleptics leads to the development of oral abnormal movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats have been widely accepted as an animal model of tardive dyskinesia. Chronic blockade of D2 inhibitory dopamine (DA) receptors localized on glutamatergic terminals in the striatum leads to the persistent enhanced release of glutamate that kills the striatal output neurons. The object of the present study was to explore the role of glutamatergic modulation on the neuroleptic-induced VCMs. Rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to produce VCMs. The neuroleptic-induced VCMs viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5 min observation period. Dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, dose dependently (0.02 and 0.05 mg/kg) reduced haloperidol-induced VCMs. Felodipine (5 and 10 mg/kg), an L-type calcium-channel blocker, also significantly reduced the VCM count. N-omega-nitro-L-arginine methyl ester (L-NAME) (25 and 50 mg/kg), a nitric oxide synthase inhibitor, also reduced the VCM count in an L-arginine-sensitive manner. In conclusion, the findings of the present study indicated NMDA receptor involvement in haloperidol-induced VCMs, and also suggested the possible involvement of calcium and nitric oxide in haloperidol-induced VCMs.

Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT 3 receptor antagonists

Tardive dyskinesia, a syndrome of abnormal, involuntary hyperkinetic movements that occurs during long-term neuroleptic therapy is a major limitation of chronic neuroleptic therapy. The pathophysiology of tardive dyskinesia is still an enigma. The objective of the present study was to elucidate the role of 5-HT 3 receptor involvement in neuroleptic-induced vacuous chewing movements in rats. Rats chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) significantly developed vacuous chewing movements, as compared to vehicle-treated controls. Both ondansetron and tropisetron dose-dependently (0.25, 0.5 and 1.0 mg/kg, i.p.) reversed the haloperidol-induced vacuous chewing movements. Serotonin acting through 5-HT 3 receptors might play a significant role in the pathophysiology of tardive dyskinesia, and 5-HT 3 receptor ligands can be exploited as novel therapeutic agents for the treatment of tardive dyskinesia.

No changes in dopamine D 1 receptor mRNA expressing neurons in the dorsal striatum of rats with oral movements induced by long-term haloperidol administration

Neuroleptic-induced vacuous chewing movements (VCM) in rats, a putative analogue to tardive dyskinesia in man, may involve degeneration within striatum as well as changes in neurotransmitter and receptor expression. In this study, we measured the expression of dopamine D 1 receptor mRNA by dorsal striatal neurons in rats with high and low level of VCM after treatment with haloperidol for 38 weeks. Both the average integrated density of the in situ hybridization signal and number of cells obtained by the stereological cell counting remained within control level, irrespective of the level of haloperidol-induced oral dyskinesia.

Effects of rating parameters on assessment of neuroleptic-induced vacuous chewing movements

Long-term administration of neuroleptics to rats produces a syndrome of vacuous chewing movements (VCMs). The validity of the VCM syndrome as a model for tardive dyskinesia (TD) in humans is unclear. This is due, in part, to inconsistencies between studies. Methods for rating VCMs have varied markedly and could account for the inconsistencies. The purpose of this study was to evaluate the importance of the different methods on VCM scores. The effects of habituation and length of rating sessions were examined in rats habituated for 2 min, 1 h, or several hours over 4 days, compared to unhabituated rats. Ratings with and without habituation were highly correlated, as were ratings from 2- and 5-min observation periods. Ratings from neuroleptic-treated rats in restraining tubes, however, were significantly correlated with unrestrained ratings only following several hours of habituation. Locomotor activity was not correlated with VCM scores. These results suggest that habituation to open cages is not an important factor in assessing VCMs. Use of restraining tubes, however, may alter scores. The lack of an habituation effect or of a relationship between activity and VCMs suggests that locomotor and oral behaviors are not necessarily in competition. Restraining rats to rate VCMs does not appear to be necessary and could alter the neurobiology of VCMs.

Persistent catalepsy associated with severe dyskinesias in rats treated with chronic injections of haloperidol decanoate.

Patients who develop persistent parkinsonism while on chronic neuroleptic therapy may be predisposed towards the development of tardive dyskinesia (TD). We investigated this issue in an animal model of TD by examining the association between catalepsy and the syndrome of neuroleptic-induced vacuous chewing movements (VCMs). VCMs were measured every 3 weeks for 33 weeks while rats received injections of haloperidol decanoate. Catalepsy was measured after the second through the seventh injections of the depot neuroleptic. There were no correlations between the severity of catalepsy scores after the second or third injections of haloperidol and the severity of the overall VCM syndrome. However, the severity of the catalepsy score following the third through seventh injections of haloperidol strongly correlated with the concurrent number of VCMs. Persistent high catalepsy scores across the six catalepsy rating sessions were strongly associated with the development of persistent severe VCMs. These findings suggest that, to the extent that persistent parkinsonian signs in humans are associated with a propensity towards the development of TD, the VCM syndrome in rats is at least a partially faithful animal model of this relationship.

Neuroleptic-induced vacuous chewing movements in rodents: incidence and effects of long-term increases in haloperidol dose

Rats treated chronically with neuroleptics develop vacuous chewing movements (VCMs), similar in some respects to tardive dyskinesia (TD) in man. The VCM syndrome was used as a model of TD to examine the ability of increased neuroleptic doses to produce long-term suppression of dyskinetic movements. The incidence and persistence of the VCM syndrome in individual rats were also assessed to look for affected and unaffected subgroups. Rats were initially treated for 15 weeks and haloperidol decanoate. For the next 21 weeks, half the group received a 50-150% increase in dose while the other half continued to receive the same dose. Animals were also followed during a 28-week withdrawal period. Total VCM ratings showed a skewed distribution, with some rats exhibiting few movements while others developed marked and persistent movements. Increasing doses did not suppress VCMs, nor did they exacerbate movements during the withdrawal period. To the extent that the VCM syndrome models TD, the absence of long-term suppression of the VCM syndrome suggests that, at this dosage range, increasing depot neuroleptic doses may not be a useful long-term strategy for TD suppression.

Neuroleptic-induced vacuous chewing movements as an animal model of tardive dyskinesia: a study in three rat strains

Vacuous chewing movements (VCMs) in three different rat strains developed at considerably different rates after 19 weeks of continual haloperidol treatment at an average daily dose of 1.5 mg/kg. Sprague Dawley (SD) rats displayed relatively high rates of VCMs with low variability, compared to Wistar (W) and Long Evan (LE) rats. Atropine decreased but did not abolish VCMs in two of the three strains (LE greater than SD). After haloperidol withdrawal, VCMs remitted gradually in all strains, but least rapidly in the SD rats. In a separate group of SD rats. VCMs were rated weekly from the start of haloperidol treatment and showed considerable interindividual variability. Even after 24 weeks of continuous haloperidol, 12 out of 32 treated rats showed no VCMs at all, while 13 out of 32 had intense movements, analogous to the clinical situation in which only some patients treated with neuroleptics develop tardive dyskinesia. These results indicate that there are individual and strain differences in the development of VCMs, and suggest that there may also be genetically determined differences in the development of tardive dyskinesia.