Dyskinesia In Rats Research Articles

Concomitant development of oral dyskinesia and memory deficits in reserpine-treated male and female mice

It has been suggested that reserpine-induced oral dyskinesia in rats may provide a new animal model of tardive dyskinesia. Both cognitive deficits and gender have been associated with the development of tardive dyskinesia. The aim of the present study was to investigate the effects of reserpine administration on the development of orofacial dyskinesia and on plus-maze discriminative avoidance task (DAT—an animal model of associative learning) in male and female mice. Male and female mice received 1.0 mg/kg reserpine or saline subcutaneously on day 1. On days 3, 6 and 8, the frequency of vacuous chewing movements (VCM) was quantified. On day 6, the DAT conditioning was performed, in a modified elevated plus-maze. In one of the enclosed arms, the animals received aversive stimulation (light and noise). On day 8, a test session was performed and the time spent by the animals in each of the enclosed arms was recorded. Our results showed that reserpine-treated male and female mice presented significantly higher VCM when compared with respective control groups in all observation days. On day 6, reserpine-treated female mice presented significantly higher VCM when compared with male mice injected with this drug. The DAT test performed on day 8 showed that the time spent in the aversive arm by saline-treated mice was significantly lower than the time spent in the non-aversive arm. This difference was not observed for reserpine-treated mice. Our results demonstrate the development of reserpine-induced oral dyskinesia in both male and female mice. While this oral dyskinesia is accompanied by a cognitive deficit in both genders, female mice tended to have more severe oral dyskinesia. It is suggested that reserpine-induced oral dyskinesia may provide a quick, simple and efficient mouse model of tardive dyskinesia.

Oral dyskinesias and morphological changes in rat striatum during long-term haloperidol administration

Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to increased glutamate release within the striatum. This may lead to excitotoxic degeneration and, as a consequence, persistent motor side effects. To investigate whether alterations in glutamatergic synapses within the striatum are associated with the development of neuroleptic-induced oral dyskinesia. Haloperidol was administered for 20 weeks, and rats with high and low levels of vacuous chewing movements (VCM) were analyzed for morphological changes with electron microscopy at three time points. At week 8, the high VCM rats had a larger nerve terminal area and lower density of nerve terminal glutamate immunoreactivity than the other groups. After 18 weeks of treatment, the nerve terminal area was increased relative to controls in both the high and low VCM groups. After discontinuation of treatment, there were no significant morphological differences between the groups, but the level of VCM was still significantly increased in the high VCM group. These results show that striatal glutamatergic transmission is affected during haloperidol treatment and the nerve terminal area and the density of nerve terminal glutamate immunoreactivity are important in determining the VCM response to haloperidol treatment. This indicates that increased glutamatergic synaptic activity in the striatum contributes to the development of human tardive dyskinesia.

Withdrawal-associated changes in peripheral nitrogen oxides and striatal cyclic GMP after chronic haloperidol treatment

The irreversible nature of haloperidol-induced tardive dyskinesia suggests a neurotoxic etiology, although the causes are unknown. Since nitric oxide demonstrates neurotoxic as well as neuroprotectant properties, and antipsychotics can inhibit nitric oxide (NO) synthase in vitro, this study investigates the NO-cGMP pathway as a pre-determining factor in chronic haloperidol-associated dyskinesia in rats. Sprague–Dawley rats were administered either water, oral haloperidol (0.25 mg/kg per day po), the guanylyl cyclase-nNOS inhibitor, methylene blue (MB; 5 mg/kg per day ip) or haloperidol plus MB for 3 weeks. In a second protocol, rats received water or haloperidol orally for 17 weeks, followed by 3 weeks withdrawal. Either saline (ip) or MB (ip) was administered for 3 weeks prior to haloperidol withdrawal. Vacous chewing movements (VCMs) were continuously monitored, followed by the determination of serum nitrogen oxides (NO x ) and striatal cGMP at week 20. Chronic haloperidol engendered significant VCMs, with acute withdrawal resulting in significantly reduced plasma NO x and striatal cGMP. Furthermore, NO x and cGMP suppression was amplified by pre-withdrawal MB administration. Sub-acute haloperidol similarly induced incremental VCMs, but without effect on NO x or cGMP. However, haloperidol plus MB also induced significantly greater VCMs with decreased cGMP compared to haloperidol alone. Thus, NO x -cGMP inhibition persists pronounced after long-term haloperidol treatment and withdrawal. MB potentiation of these effects suggests that haloperidol inhibits a NO-dependent neuro-protective response to oxidative stress in the striatum that may pre-determine TD development.

Reduced number of striatal neurons expressing preprosomatostatin mRNA in rats with oral dyskinesias after long-term haloperidol administration

Neuroleptic-induced oral dyskinesia in rats, a putative analogue to human tardive dyskinesia, may be due to degeneration within the striatum. Using unbiased stereological methods, a decreased number of striatal neurons expressing preprosomatostatin mRNA was observed only in rats that developed pronounced oral dyskinesias after 30 weeks of haloperidol administration. The amount of preprosomatostatin mRNA in each striatal neuron, measured in terms of optical densities of individual neurons, was not affected by haloperidol. A tendency toward a reduction in the number of NADPH-diaphorase positive neurons was observed in rats receiving haloperidol. These results indicate that the mechanism by which neuroleptics induce oral dyskinesias in rats, and perhaps tardive dyskinesia in humans, involves a functional disruption and possibly damage of a subpopulation of interneurons in the striatum.

Effects of buspirone on an animal model of tardive Dyskinesia

Queiroz, Claudio M.T. and Roberto Frussa-Filho: Effects of Buspirone on An Animal Model of Tardive Dyskinesia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1999, 23, pp. 1405–1418. 1. 1. The effects of buspirone were studied on an animal model of tardive Dyskinesia I.e., the quantification of orofacial dyskinesia in rats repeatedly treated with reserpine. 2. 2. Rats were co-treated with saline [SAL] or buspirone [BUS] (3. 0 mg/Kg I.p., twice daily) and vehicle [VEH] or reserpine [RES] (0. 1 mg/Kg S.c., once every other day) for 19 days. On the day 20, the animals were observed for quantification of the behavioral parameters of orofacial dyskinesia: tongue protrusion and vacuous chewing movements frequencies and duration of twitching of the facial musculature. 3. 3. Rats of the SAL+RES group exhibited a significant increase in the three behavioral parameters of orofacial dyskinesia relative to the rats of the SAL+VEH group. However, animals of the BUS+RES group showed only an increased frequency of vacuous chewing movements when compared to animals of the SAL+VEH group. In addition, the duration of the facial twitching was significantly decreased in the BUS+RES group in relation to rats of the SAL+RES group. There were no significant differences in the orofacial parameters between the BUS+VEH and the SAL+VEH groups. 4. 4. Because it was also verified that chronic buspirone treatment was able to increase apomorphine-induced yawning behavior, the possibility is raised that buspirone attenuates reserpine-induced orofacial dyskinesia through the development of dopamine autoreceptor supersensitivity.

Coenzyme Q10 Does Not Prevent Oral Dyskinesias Induced by Long-Term Haloperidol Treatment of Rats

Tardive dyskinesia (TD) is a debilitating side effect of long-term treatment with neuroleptics with an unclear pathophysiologic basis. It has been proposed that TD may be a result of neuroleptic-induced oxidative stress. To investigate this hypothesis, we studied if neuroleptic-induced oral dyskinesias in rats, a putative analogue to human TD, could be prevented by the antioxidant coenzyme Q10 (CoQ10). Rats received 16 weeks of treatment with haloperidol decanoate (HAL) IM alone or together with orally administered CoQ10, and the behavior was recorded during and after treatment. HAL significantly increased the level of oral dyskinesias, and the increase persisted for 12 weeks after drug withdrawal. Cotreatment with CoQ10 did not attenuate the development of HAL-induced oral dyskinesia. Despite adequate absorption of orally administered CoQ10, shown by the increased serum levels of CoQ10, no increase of either CoQ10 or coenzyme Q9 was detected in the brain. These results suggest that cotreatment with CoQ10 does not inhibit the development of HAL-induced oral dyskinesias in rats, and that further studies seem to be needed in order to clarify the pharmakokinetics of CoQ10 in rats.

The relationship between oral dyskinesias produced by long-term haloperidol treatment, the density of striatal preproenkephalin messenger RNA and enkephalin peptide, and the number of striatal neurons expressing preproenkephalin messenger RNA in rats

Neuroleptic-induced oral dyskinesias in rats, a putative analogue to human tardive dyskinesia, may be due to excitotoxic degeneration within the striatum. Haloperidol treatment for 34 weeks increased the optical density of preproenkephalin messenger RNA in individual striatal neurons and enkephalin peptide in the neuropil, regardless of the level of oral dyskinesia produced. However, using unbiased stereological methods, an increased number of striatal neurons expressing preproenkephalin messenger RNA was observed only in rats that did not develop pronounced oral dyskinesias during haloperidol treatment. Said in another manner, the haloperidol-treated animals that developed pronounced oral dyskinesias, failed to produce an increase in the number of neurons expressing preproenkephalin messenger RNA. These results indicate that the mechanism by which neuroleptics induce oral dyskinesias in rats, and perhaps tardive dyskinesia in humans, involves a functional disturbance or even damage to a subpopulation of enkephalinergic neurons in the striatum.

Chronic Olanzapine or Sertindole Treatment Results in Reduced Oral Chewing Movements in Rats Compared to Haloperidol

Chronic haloperidol treatment typically produces late-onset, purposeless oral chewing movements in laboratory rats with a prevalence of 40 to 60%. Chronic clozapine does not produce these movements. Based on the phenomenologic and pharmacologic similarities between these rat chewing movements and human tardive dyskinesia (TD), the animal movements are often used as a model of tardive dyskinesia (TD). Here we report results of the association of oral chewing movements in rats with chronic administration of two new antipsychotic drugs, olanzapine and sertindole. Because each of these antipsychotic drugs has a very low incidence of acute Parkinsonism in human studies, they are candidates for showing a low tardive dyskinesia risk. Neither new drug produced a significant incidence of haloperidol-like chewing in rats, nor did movement ratings after their chronic administration differ from placebo; whereas, haloperidol produced a 60% prevalence of purposeless chewing and a prevalence significantly increased from placebo. This low rate of oral dyskinesias in rats is consistent with several of the preclinical characteristics of the drugs and correlates with their low acute motor side effects in clinical trials. We propose, although have not yet tested in humans, that these animal results will predict low TD liability of these drugs.

Treatment of depression in schizophrenia : L. Lykouras. Athens University, Department of Psychiatry, Eginition Hospital, Athens 115 28 Greece

Recently, we have described the beneficial effects of Diphenyl diselenide, an organochalcogen with glutathione peroxidase-like activity, on reserpine-induced orofacial dyskinesia in old rats. In this study, our aim was to examine the effects of diselenide on haloperidol-induced orofacial dyskinesia in rats. Male wistar rats received one single dose of Haloperidol decanoate (57 mg/kg/im) or control. After this dose, the animals received daily administration of diphenyl diselenide (1, 5 or 10 mg/kg/sc) or control, during 28 days. Twenty-four hours after the last diselenide or control solution injection, all the rats were observed for quantification of oral dyskinesia through the frequency of vacuous chewing movements (VCM) and tongue protrusion (TP) and the duration of facial twitching (FT). Haloperidol caused a significant increase in VCM, TP and FT observed in the 4 weekly evaluations (p < 0.05). The co-administration of diselenide (5 mg/kg) reversed this effect for all the parameters in four behavioral sessions.The results of the present study demonstrate the possible protective activity of diphenyl diselenide on haloperidol-induced orofacial diskinesia. This effect is in accordance to the involvement of neurotoxicity in orofacial dyskinesia and suggest that studies be continued with new antioxidant compounds.

Effects of Age on a New Animal Model of Tardive Dyskinesia

The effects of age were studied on a new animal model of tardive dyskinesia, i.e., the quantification of oral dyskinesia in rats repeatedly treated with reserpine. Adult and old rats received two injections of reserpine (0.5 or 1.0 mg/kg s.c.) or vehicle, separated by 48 h. One, 10, 25 and 40 days after the second injection of reserpine or vehicle, the animals were observed for quantification of the behavioral parameters of oral dyskinesia: tongue protrusion and vacuous chewing movement frequencies and duration of twitching of the facial musculature. Phenomenologically, control old rats and reserpine-treated adult animals showed very similar oral dyskinesia. When compared to control adult rats, the significant increase in tongue protrusion frequency induced by reserpine treatment was more persistent in the old rats than in the adult animals. Because it is well known that age increases the persistence of tardive dyskinesia, our data provide further support for the validation of reserpine-induced oral dyskinesia as an animal model of tardive dyskinesia. In addition, the possibility is raised that a common pathophysiological mechanism may underlie tardive dyskinesia and age- and reserpine-induced oral dyskinesia.

Ultrastructural correlates of haloperidol-induced oral dyskinesias in rat striatum.

Neuroleptics given chronically to rats induce behavioral sequelae which mimic tardive dyskinesia in some respects. The intent of this study was to investigate the ultrastructural correlates of oral dyskinesias (vacuous chewing movements [VCMs]), induced by chronic haloperidol treatment. After 6 months of treatment, rats were divided into low or high VCM groups. Rats in the high VCM group were either sacrificed on drug or were withdrawn from drug for 4 weeks. Ultrastructural analyses of the striatum indicated that synaptic density: 1) was significantly decreased in both the low and high VCM groups compared to normal controls; 2) was more profoundly decreased in the high VCM group as compared to the low VCM group; and 3) recovered to normal following drug withdrawal. Compared to controls, the density of asymmetric synapses was reduced by a similar magnitude in both the low and high VCM groups, suggesting that this change is a result of haloperidol treatment and independent of VCMs. Conversely, the density of symmetric synapses was reduced compared to normal, only in the high VCM group, suggesting that this change is specifically related to the expression of VCMs. In addition, mitochondrial profiles were hypertrophied and less frequent in the high VCM group in comparison to controls; size, but not number, recovered following drug withdrawal. These results identify distinct ultrastructural correlates of chronic haloperidol treatment that are unique to rats that develop VCMs and suggest that these ultrastructural features may play a role in the pathophysiology of oral dyskinesias in rats.

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.

Drug-induced oral dyskinesias in rats after traditional and new neuroleptics.

Tardive dyskinesia (TD) is a serious human side effect of neuroleptic treatment in psychotic disorders. Although the etiology is clear (i.e. chronic neuroleptic drugs), its pathophysiology has not yet been satisfactorily explained. This is important not only theoretically but also to inform drug development, allowing the introduction of antipsychotic compounds without TD liability. The development of an animal condition which putatively models these delayed onset dyskinesias, has provided a technique to differentiate between neuroleptic drug effect and dyskinesia correlates. We report here the development of oral dyskinesias in rats in response to a number of different neuroleptics, which have a range of neurochemical and clinical characteristics. Traditional neuroleptics (e.g. haloperidol) produced rat oral dyskinesias, in an open-cage environment. Clozapine, while it produced an increased rate of oral movements, showed a significantly decreased potency in this model. SCH23390 (D1 antagonist) neither produced the oral movements nor modified their onset by coadministration with raclopride. These data replicate and extend other similar studies in the literature. They suggest that clozapine differs from traditional neuroleptics with respect to motor side effects.

Cysteamine attenuates iminodipropionitrile (IDPN) induced dyskinesia in rats.

The present investigation was undertaken to study the effect of cysteamine on experimental dyskinesia in rats. The movement disorders were produced by intraperitoneal administration of iminodipropionitrile (IDPN) in the dose of 100 mg/kg per day for 11 days. Cysteamine was administered (i.p.), daily 30 minutes before IDPN in the doses of 25 mg/kg, 50 mg/kg and 100 mg/kg bodyweight in three different groups of rats. Twenty four hours after the last dose of IDPN, animals were observed for neurobehavioural changes including vertical and horizontal head weaving, circling, backwalking, grip strength and righting reflex. Immediately after behavioural studies brain specimens were collected for analysis of vitamin E and total glutathione levels. The results of behavioural studies showed that co-treatment with cysteamine protected rats against IDPN-induced dyskinesia. Our biochemical studies showed that IDPN produced a depletion of vitamin E in cerebrum, cerebellum and brain stem. Concomitant treatment with cysteamine in doses of 50 and 100 mg/kg attenuated IDPN-induced decrease in vitamin E in cerebrum and cerebellum. There was a significant decrease in cerebral glutathione in IDPN treated rats, which was attenuated by cysteamine. No significant change was observed in the glutathione levels in cerebellum and brain stem. Further studies are deemed necessary to elucidate the mode of action of cysteamine and to determine therapeutic and/or prophylactic value of this drug in the treatment of movement disorders.

Dipyridamole attenuates the development of iminodipropionitrile-induced dyskinetic abnormalities in rats

The present investigation was undertaken to study the effect of dipyridamole on experimental dyskinesia in rats. The movement disorders were produced by intraperitoneal administration of iminodipropionitrile (IDPN) in the dose of 100 mg/kg per day for 12 days. Dipyridamole was administered orally, daily 30 min before IDPN in the doses of 0.5 g/kg, 1 g/kg, and 1.5 g/kg bodyweight in three different groups of rats. Twenty-four hours after the last dose of IDPN, animals were observed for neurobehavioral changes including vertical and horizontal head weaving, circling, backwalking, grip strength, and righting reflex. Immediately after behavioral studies brain specimens were collected for analysis of vitamin E, conjugated dienes, and lipid hydroperoxides as indices of oxygen-derived free radical (OFR) production. Our results showed that concurrent use of dipyridamole significantly protected rats against IDPN-induced neurobehavioral changes in a dose-dependent manner. Treatment of rats with dipyridamole inhibited IDPN-induced decrease of vitamin E and increase in conjugated dienes and lipid hydroperoxides in brain. These findings suggest the involvement of OFR in dipyridamole induced protection against the development of IDPN dyskinesia. Further studies are warranted to determine the role of dipyridamole as a prophylactic agent against the drug induced dyskinetic abnormalities.

Dose-dependent differences in the development of reserpine-induced oral dyskinesia in rats: support for a model of tardive dyskinesia

Rats treated with reserpine develop spontaneous orofacial dyskinesia that has features similar to tardive dyskinesia (TD) in humans. In contrast to TD, however, reserpine-induced oral dyskinesia develops rapidly reaching a maximal level within 3 days at a dose of 1 mg/kg per day. The present study examined whether rats administered lower doses of reserpine would develop the oral dyskinesia at a slower rate, similar to the protracted development of TD. Rats were administered 0, 0.01, 0.05, 0.1, or 1.0 mg/kg reserpine subcutaneously every other day for 100 days. Oral dyskinesia was measured by recording the incidence of tongue protrusions for 30 min on days 1, 4, 10, 20, 40, 60, and 100. The time course of the development of reserpine-induced oral dyskinesia varied dose-dependently. The response was evident within 4 days at 1 mg/kg, within 20 days at 0.1 mg/kg, within 60 days at 0.05 mg/kg, and was not evident at 0.01 mg/kg at any time during the 100 days of treatment. The protracted development of reserpine-induced oral dyskinesia at the lower doses is consistent with TD. Doses of reserpine that produced an increase in tongue protrusions also produced a 90-95% depletion of dopamine and an increase in the ratio of dopamine metabolites to dopamine in the caudate-putamen. The disruption of dopamine neurotransmission may be involved in development of the oral dyskinesia. Furthermore, it is suggested that the 1 mg/kg dose of reserpine may induce neurochemical changes similar to that produced by long-term neuroleptic treatment, but at an accelerated rate, thereby providing a new efficient model of TD.

Effect of selenium and vitamin E on iminodipropionitrile induced dyskinesia in rats.

The present study was undertaken to determine the effect of combination of selenium and vitamin E on experimentally induced dyskinesia in rats. The dyskinetic syndrome was produced in 4 groups of 6 male rats each weighing 250-300g by intraperitoneal (ip) administration of iminodipropionitrile (IDPN) in doses of 100 mg/kg body weight daily for 12 days. A group of 6 rats (group 1) served as control and received normal saline only. The rats in group 2 (IDPN only) received normal saline (ip) 30 minutes before the administration of IDPN. The animals in groups 3, 4 and 5 received selenous acid (5 mumol/kg), vitamin E (500 mg/kg p.o.) and a combination of selenous acid and vitamin E respectively, daily, 30 minutes before IDPN for 12 days. Twenty four hours after the last dose of IDPN, the dyskinetic behavior including vertical head movements (retrocollis), horizontal head movements (laterocollis), circling and backwalking of each rat was studied for a period of 10 minutes. Immediately after behavioral studies, the animals were sacrificed and brains were dissected out for the analysis of conjugated dienes, lipid hydroperoxides and vitamin E. The results of this study showed that treatment of rats with IDPN only for 12 days produced dyskinetic syndrome in all the rats characterized by vertical and horizontal head movements, circling and backwalking. Concomitant treatment of rats with vitamin E and selenium individually reduced IDPN induced dyskinesia, and the symptoms were almost completely absent when the combination of these two agents was used.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of striatal extracellular dopamine and dopamine metabolites by microdialysis in haloperidol-treated rats exhibiting oral dyskinesia.

Rats that had received continuous, chronic haloperidol (HAL) for 32 weeks were mentioned for changes in oral movements as determined by Fast Fourier analysis of jaw movements recorded with a computerized video analysis system. Beginning at 24 weeks of administration, HAL-treated animals exhibited a pattern of significant increases in oral movement activity in the 1 to 3 Hz range and decreases in the 5 to 8 Hz range when compared to control animals. The release and metabolism of dopamine (DA) in the striatum of these animals was then assessed using intracranial microdialysis during week 32 of HAL administration and 3 days after withdrawal of HAL. Basal extracellular concentrations of the DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid were significantly increased in the HAL-treated rats during continuous HAL administration. Three days after withdrawal from HAL, no difference was seen in basal extracellular concentrations of any of the analytes. No difference in the magnitude of DA release was seen between groups following local application of amphetamine (10 microM) through the dialysis probe during or after chronic HAL administration. These results confirm previous findings that long-term HAL administration produces increased DA turnover during HAL administration, but that this increase does not persist following HAL withdrawal. The increased striatal DA turnover seen during chronic HAL administration may have relevance to the development of late-onset neuroleptic-induced dyskinesia in rats.

A study on the action of two calcium channel blockers (verapamil and flunarizine) upon an experimental model of tardive dyskinesia in rats.

Tardive dyskinesia (TD), a serious complications of neuroleptic chronic use, has no effective therapy yet. We performed an experiment to study the action on TD, of the calcium channel blockers (CCB) drugs, verapamil and flunarizine. We obtained the TD model in rats, administering haloperidol for a 21-day period. After this, the stereotyped movement induced by apomorphine was rated. The CCB drugs were administered in acute (in the 28th day) and chronic (for 8 days, after the 25th day) experiments. Acutely, verapamil increased the stereotyped behaviour, and promoted a reduction of it in the chronic experiment. The results suggest that CCB drugs should be tested in clinical trials of TD.

Co-administration of progabide inhibits haloperidol-induced oral dyskinesias in rats

Vacuous chewing movements in rats may be an animal analogue of the human motor disorder, tardive dyskinesia. The movements are phenomenologically and pharmacologically similar to tardive dyskinesia. The pathophysiology of these involuntary oral movements, and perhaps of tardive dyskinesia, are likely to include both dopamine receptor changes, and alterations in GABA (γ-aminobutyric acid) system function. In an attempt to test the involvement of GAVA system dysfunction in these movements, we treated rats chronically with water alone, haloperidol alone, the GABA agonist progabide alone, and haloperidol plus progabide. Sprague-Dawley rats received haloperidol (1.5 mg/kg per day) in their drinking water and progabide (100 mg/kg per day) in their food for 12 months. After 12 months of treatment, haloperidol had induced vacuous chewing movements when administered alone, but the prevalence of the movements was decreased by 40% with the coadministration of progabide. Moreover, the haloperidol-progabide-treated animals did not merely demonstrate movement suppression but actual inhibition of movement onset, as determined by an additional progabide-withdrawal experiment. These data would suggest that progabide and perhaps other GABAmimetic compounds can prevent the development of tarkive dyskinesia in man.