Increase In Vacuous Chewing Movements Research Articles

Ginkgo biloba leaf extract and alpha-tocopherol attenuate haloperidol-induced orofacial dyskinesia in rats: Possible implication of antiapoptotic mechanisms by preventing Bcl-2 decrease and Bax elevation

BackgroundTardive dyskinesia (TD) is a serious side effect of long-term administration of typical neuroleptics, such as haloperidol. The pathophysiology of TD remains unclear, but the experimental evidence suggests that free radical-induced neuronal apoptosis in the basal ganglia may play an important role. PurposeThis study was to investigate changes in Bax and Bcl-2 expression levels in TD-associated brain regions and the effects of the antioxidant EGb761 on Bax and Bcl-2 levels in an animal model of TD. MethodsThirty-two rats were randomly divided into four study groups: saline control (saline), haloperidol-alone (haloperidol), EGb761-haloperidol (EGb), and alpha-tocopherol-haloperidol (vitamin E). Rats were treated with daily intraperitoneal haloperidol injections (2 mg/kg/day) for 5 weeks. EGb761 (50 mg/kg/day) and alpha-tocopherol (20 mg/kg/day) were then administered for another 5 weeks during the withdrawal period. Behavioral assessments were performed, and Bax and Bcl-2 protein expression levels were immunohistochemically analyzed in four brain regions, including the prefrontal cortex, striatum, substantia nigra, and globus pallidum. ResultsWe found that increased vacuous chewing movements (VCMs) were associated with increased proapoptotic Bax protein expression, decreased antiapoptotic Bcl-2 protein expression, and an increased Bax/Bcl-2 ratio. EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression, and decreased the Bax/Bcl-2 ratio. ConclusionsThese results demonstrate that long-term haloperidol administration may affect Bcl-2 protein family expression and promote neuronal apoptosis in the basal ganglia. In combination with their antioxidant capacity, EGb761 and alpha-tocopherol's antiapoptotic effects through Bcl-2 might account for the symptom improvement observed in haloperidol-induced TD rats.

Ginkgo biloba and vitamin E ameliorate haloperidol-induced vacuous chewingmovement and brain-derived neurotrophic factor expression in a rat tardive dyskinesia model

Neurodegeneration may be involved in the development of tardive dyskinesia (TD), and low levels of brain-derived neurotrophic factor (BDNF) may play a role. Ginkgo biloba (EGb761), a potent antioxidant, may have neuroprotective effects. We hypothesized that there would be decreased BDNF expression in TD, but that treatment with EGb761 would increase BDNF expression and reduce TD manifestations in a rat model. Forty rats were treated with haloperidol (2mg/kg/day via intraperitoneal injections) for 5weeks. EGb761 (50mg/kg/day) and vitamin E (20mg/kg/day) were then administered by oral gavage for another 5weeks, and we compared the effects of treatment with EGb761 or vitamin E on haloperidol-induced vacuous chewing movements (VCMs) and BDNF expression in four brain regions: prefrontal cortex (PFC), striatum (ST), substantia nigra (SNR), and globus pallidus (GP). Our results showed that haloperidol administration led to a progressive increase in VCMs, but both EGb761 and vitamin E significantly decreased VCMs. Haloperidol also decreased BDNF expression in all four brain regions, but both EGb761 and vitamin E administration significantly increased BDNF expression. Our results showed that both EGb761 and VE treatments exerted similar positive effects in a rat model of TD and increased BDNF expression levels in the four tested brain regions, suggesting that both EGb761 and vitamin E improve TD symptoms, possibly by enhancing BDNF in the brain and/or via their free radical-scavenging actions.

Extract of Ginkgo biloba is equivalent to vitamin E in attenuating and preventing vacuous chewing movements in a rat model of tardive dyskinesia

Free radical-mediated abnormalities may contribute toward the pathogenesis of tardive dyskinesia (TD). Many studies have reported the protective antioxidant and free radical-scavenging activities of extract of Ginkgo biloba (EGb761) against free radical-induced cell damage and dysfunction. This study aimed to compare the efficacy of EGb761 with that of vitamin E for the prevention and treatment of TD in a rat model. We carried out two studies. First, rats were injected with haloperidol (2 mg/kg intraperitoneally) daily for 5 weeks. EGb761 (50 mg/kg/day) or vitamin E (20 mg/kg/day) were then administered for another 5 weeks, and their effects on vacuous chewing movements (VCMs) were compared. Second, we compared 10 weeks of haloperidol alone with 10 weeks of haloperidol plus EGb761 or vitamin E. The administration of haloperidol led to a progressive increase in VCMs, which peaked at week 5. In study one, EGb761 and vitamin E, administered by an oral gavage for 5 weeks during withdrawal from chronic haloperidol treatment, decreased VCMs significantly, showing 83.8 and 91.0% reduction, respectively, compared with the haloperidol-alone group. In study two, the concomitant administration of EGb761 and vitamin E led to significantly fewer VCMs, by 64.4 and 73.9%, respectively, compared with the haloperidol-alone group. There was no significant difference in either study between EGb761 and vitamin E treatment. EGb761 shows promise for the prevention and treatment of TD in a rat model with a magnitude that was similar to that of vitamin E.

Beneficial effects of an innovative exercise model on motor and oxidative disorders induced by haloperidol in rats

Here we evaluate the influence of a new exercise protocol on movement disorders induced by neuroleptic drugs. In this animal model, involuntary movements are closely related to neuronal degeneration and oxidative stress (OS) that can be caused by pre-synaptic D2 receptor blockade increasing dopamine (DA) metabolism. The increase in vacuous chewing movements (VCM) and the reduced locomotor activity induced by haloperidol treatment (12 mg/kg-im, once a week for 4 weeks) was prevented by exercise, 5 times per week, which was initiated four weeks before the first haloperidol administration. Exercise training also prevented the increase of haloperidol-induced lipid peroxidation in the cortex and subcortical region and recovered the catalase activity in the subcortical region. There was a negative correlation between catalase activity in the subcortical region and the VCM frequency (r = 0.50, p < 0.05), as well as a positive correlation between VCM frequency and lipid peroxidation in the cortex (r = 0.64, p < 0.05) and subcortical region (r = 0.71, p < 0.0001). Both haloperidol and exercise increased DA uptake in the striatum, while the co-treatment (exercise plus haloperidol) reduced it. The striatal DA uptake correlated negatively with catalase activity (r = 0.51, p < 0.05), indicating a relationship between oxidative damage and the function of the transporter in the striatum. Our findings show that physical exercise can modulate dopamine uptake, especially when it is altered, and reveal the benefit of this new exercise protocol in the prevention of movement disorders related to oxidative damage.

Protective effect of Morus alba leaves on haloperidol-induced orofacial dyskinesia and oxidative stress

Long-term treatment with haloperidol, a typical neuroleptic, induces neurodegeneration caused by excitotoxicity and oxidative stress, which play an important role in the development of orofacial dyskinesia. In the present investigation, an attempt has been made to examine the effect of a concomitant treatment of methanol extract of Morus alba Linn. (Moraceae) leaves (100–300 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) on an animal model of tardive dyskinesia. Rats were treated for 21 days with haloperidol and Morus alba extract; vacuous chewing movements and tongue protrusions were counted. The extract attenuated the increase in vacuous chewing movements and tongue protrusions induced by haloperidol, which were quantified on day 22. The extract showed a marked effect on behavioral parameters altered by haloperidol treatment. Similar treatment with extract attenuated haloperidol-induced lipid peroxidation and nitrite and normalized superoxide dismutase, catalase, and protein in comparison to the control group. The results suggest a protective effect of Morus alba extract against haloperidol-induced orofacial dyskinesia and oxidative stress.

Effects of ω-3 Essential Fatty Acids (ω-3 EFAs) on Motor Disorders and Memory Dysfunction Typical Neuroleptic-induced: Behavioral and Biochemical Parameter

The effects of fish oil supplementation on motor disorders, memory dysfunction, and lipid peroxidation (LP) induced by typical neuroleptics were studied. Wistar rats received a suspension prepared with fish oil containing omega-3 fatty acids, water, and Tween 80 (1%) in the place of drinking water (FO group) or vehicle (C group) for 8 weeks. After 4 weeks of treatment, half of the animals of both groups were treated with haloperidol (H and FO + H groups; experiment 1), fluphenazine (F and FO + F groups; experiment 2), or vehicle (C group), administered once a week (12 mg/kg/im) for 4 weeks, maintaining the treatment with FO. Extrapyramidal motor disorders by haloperidol and fluphenazine were observed by an increase in vacuous chewing movements and catalepsy (P < 0.05). These effects were reduced by FO treatment (P < 0.05). Both neuroleptics displayed impairment in memory retention observed by latency time to find the original location of platform in water-maze task, after 4 days of training performed in the last treatment week. This effect was reduced by FO (P < 0.05) to both haloperidol and fluphenazine treatments. Haloperidol increased the LP in plasma and hippocampus, and these effects were decreased by FO treatment (P < 0.05). Fluphenazine increased the LP in plasma and substantia nigra, which were completely decreased by FO treatment (P < 0.05). The FO decreased the motor disorders, memory dysfunction, and oxidative damage typical neuroleptic-induced. Our results indicate that FO exhibits a neuroprotector role useful on diseases related to oxidative damages, and may be considered in the prevention of motor and memory side effects induced by the antipsychotic treatment.

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.

Influence of chronic exercise on reserpine-induced oxidative stress in rats: Behavioral and antioxidant evaluations

Several neurological diseases are related to oxidative stress (OS) and neurotoxicity. Considering that physical exercise may exert beneficial effects on antioxidant defenses, our objective was to evaluate the influence of a swimming exercise on an OS animal model (reserpine-induced orofacial dyskinesia). In this model, the increased dopamine metabolism can generate OS and neuronal degeneration, causing involuntary movements. The increase in vacuous chewing movements and facial twitching caused by reserpine (1 mg/kg sc) was partially prevented by exercise. An increase in catalase activity and a decrease in GSH levels were observed in the striatum. Physical training did not change the effects of reserpine on catalase, however it partially recovered GSH. Exercise per se caused a significant GSH decrease. There was a positive correlation between catalase and OD ( r = 0.41; r = 0.47, P < 0.05) and a negative correlation between GSH and OD ( r = 0.61; r = 0.71, P < 0.05). These results reveal the benefit of exercise in attenuating the motor disorder related to OS.

Role of calcium-independent phospholipase A2 in cortex striatum thalamus cortex circuitry–enzyme inhibition causes vacuous chewing movements in rats

High levels of calcium independent phospholipase A2 (iPLA2) are present in certain regions of the brain, including the cerebral cortex, striatum, and cerebellum (Ong et al. 2005). The present study was carried out to elucidate a possible role of the enzyme in the motor system. The selective iPLA2 inhibitor bromoenol lactone (BEL), the nonselective PLA2 inhibitor methyl arachidonyl fluorophosphonate (MAFP), and an antisense oligonucleotide were used to interfere with iPLA2 activity in various components of the motor system. Control animals received injections of carrier (phosphate buffered saline, PBS) at the same locations. The number of vacuous chewing movements (VCM) was counted from 1 to 14 days after injection. Rats that received BEL and high-dose MAFP injections in the striatum, thalamus, and motor cortex, but not the cerebellum, showed significant increase in VCM, compared to those injected with PBS at these locations. BEL-induced VCM were blocked by intramuscular injections of the anticholinergic drug, benztropine. Increased VCM was also observed after intrastriatal injection of antisense oligonucleotide to iPLA2. The latter caused a decrease in striatal iPLA2 levels, confirming a role of decreased enzyme activity in the appearance of VCM. These results suggest an important role for iPLA2 in the cortex-striatum-thalamus-cortex circuitry. It is postulated that VCM induced by iPLA2 inhibition may be a model of human parkinsonian tremor.

U-74500A (Lazaroid), a 21-aminosteroid attenuates neuroleptic-induced orofacial dyskinesia

21-Aminosteroid, or lazaroid, is one of a novel class of antioxidant drugs designed to inhibit iron-dependent lipid peroxidation in biological lipid environments. They have shown promising results in several animal models of traumatic, ischemic and hemorrhagic injury of the central nervous system. Neuroleptic-induced orofacial dyskinesia is an animal model of tardive dyskinesia whose pathophysiology has been related to oxidative stress in the basal ganglia. In this study, we have examined the protective role of U-74500A [pregna-1,4,9(11)-triene-3,20-dione, 21-(4-(5,6-bis(diethylamino)-2-pyridinyl)-1-piperazinyl)-16-ethyl-HCl (16-alpha)], a 21-aminosteroid having antioxidant property in attenuating the behavioral and biochemical effects of chronic haloperidol and chlorpromazine administration. Haloperidol (1 mg/kg/day i.p.) and chlorpromazine (5 mg/kg/day i.p.) administered for 21 days caused a significant increase in vacuous chewing movements (VCMs), tongue protrusion (TP) and the number of facial twitchings (FT) observed on day 22. U-74500A (1, 2 and 5 mg/kg i.p.), administered every day, along with haloperidol (1 mg/kg/day i.p.) and chlorpromazine (5 mg/kg/day), attenuated the increase of VCMs and related behaviors on day 22. Haloperidol and chlorpromazine significantly increased lipid peroxidation in various brain areas such as the cortex, striatum and subcortical parts characterized by an increase in MDA levels. The coadministration of U-74500A limited the effect of haloperidol and chlorpromazine on MDA levels in the cortex and striatum but not in the subcortical parts. U-74500A, an aminosteroid, may have therapeutic use in typical neuroleptic-induced tardive dyskinesia-like effects.

Effects of diphenyl–diselenide on orofacial dyskinesia model in rats

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.

Ebselen attenuates haloperidol-induced orofacial dyskinesia and oxidative stress in rat brain

Haloperidol-induced orofacial dyskinesia is an animal model of tardive dyskinesia whose pathophysiology has been related to basal ganglia oxidative stress. In this study the authors examined whether ebselen, an antioxidant organochalcogen with glutatione peroxidase-like activity, changes the behavioral and neurochemical effect of sub-chronic haloperidol administration. Haloperidol administered (12 mg/kg/week, sc) for 4 weeks caused a significant increase in vacuous chewing movements (VCMs), tongue protrusion (TP) and the duration of facial twitching (FT) observed in 4 weekly evaluations ( p < 0.05). Ebselen (30 mg/kg, ip), administered every other day, along with haloperidol (12 mg/kg/week, sc) once weekly, reversed the increase of VCMs and FT in four weekly evaluations ( p < 0.05), while TP frequency was reverted in the 2nd, 3rd, and 4th week. After the treatments and behavioral observation, biochemical parameters in segments of the brain were analyzed. Haloperidol significantly increased the thiobarbituric acid-reactive species (TBARS) levels in the cortex, striatum and subcortical parts of the brain. The co-administration of ebselen reversed the effect of haloperidol on TBARS production in cortex and striatum. The results of the present study clearly indicate that ebselen has a protective role against haloperidol-induced orofacial dyskinesia and reverses the increase in TBARS production caused by haloperidol administration. Consequently, the use of ebselen as a therapeutic agent for the treatment of tardive dyskinesia should be considered.

Blockade of nigral and pallidal opioid receptors suppresses vacuous chewing movements in a rodent model of tardive dyskinesia

Chronic neuroleptic treatment leads to the development of tardive dyskinesia in 20–30% of patients. While the pathogenesis of tardive dyskinesia remains elusive, altered opioid peptide function in striatal projection pathways of the basal ganglia has been implicated. Using a rodent model of vacuous chewing movements induced by chronic neuroleptic administration, we investigated regional involvement of opioid transmission in tardive dyskinesia. We examined the role of dynorphin in the direct striatonigral pathway by infusing nor-binaltorphimine, a selective κ opioid receptor antagonist, into the substantia nigra pars reticulata. As well, infusions of naloxone (a non-specific opioid receptor antagonist), D-Phe-Cys-Tyr- D-Trp-Orn-Thr-Pen-Thr amide (CTOP; a μ opioid receptor antagonist) or naltrindole (a δ opioid receptor antagonist) into the globus pallidus were used to establish the contribution of the striatopallidal pathway. Chronic fluphenazine treatment (25 mg/kg i.m. every 3 weeks for 18 weeks) resulted in a robust increase in vacuous chewing movements. Infusion of nor-binaltorphimine (5.0 nmol) into the substantia nigra pars reticulata significantly attenuated vacuous chewing movements. Infusion of naloxone (0.5 and 2.0 nmol) into the globus pallidus also significantly attenuated vacuous chewing. Infusion of naltrindole into the globus pallidus blocked vacuous chewing at all doses administered (0.5, 1.0, 2.0 nmol) while CTOP was only effective at the two higher doses. From these results we suggest that increases in dynorphin in the direct striatonigral pathway and enkephalin in the indirect striatopallidal pathway following chronic neuroleptic administration are both likely to contribute to tardive dyskinesia.

Oral dyskinesias and striatal lesions in rats after long-term co-treatment with haloperidol and 3-nitropropionic acid

The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitropropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropionic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-nitropropionic acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid+haloperidol group and for four weeks in the 3-nitropropionic acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.

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.

The Neurotensin Antagonist SR 48692 Fails to Modify the Behavioural Responses to a Dopamine D1 Receptor Agonist in the Rat

The effects of the neurotensin antagonist SR 48692 on the behavioural responses to the dopamine D1 receptor agonist SKF 38393 were investigated in the rat. SKF 38393 (5 mg/kg s.c.) elicited vacuous chewing movements (VCMs) and grooming, which were unaffected by SR 48692 (50 μg/kg i.p.). The dopamine D2 receptor antagonist raclopride (0.5 mg/kg s.c.) elicited a small increase in VCMs in animals treated with SR 48692 and attenuated grooming induced by SKF 38393. These effects were not otherwise modified by SR 48692.We conclude that VCMs induced by acute administration of a dopamine D1 receptor agonist are unlikely to be dependent upon enhanced release of neurotensin in the striatum or its projections. This is in contrast to the vacuous chewing response which emerges following chronic administration of neuroleptics, which is attenuated by a neurotensin receptor antagonist. Thus, inasmuch as chronic neuroleptic-induced VCMs in the rat may be analogous to tardive dyskinesia in humans, the responses induced by acute administration of a D1 agonist to the rat cannot be used as a model of this disorder. Furthermore, the behavioural effects of chronic neuroleptic administration reflect more than a simple shift in the balance of D1 versus D2 receptor stimulation. © 1997 Elsevier Science Ltd. All rights reserved.

Inhibition by memantine of the development of persistent oral dyskinesias induced by long-term haloperidol treatment of rats.

1. Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if neuroleptic-induced excessive stimulation of striatal glutamate receptors may underlie TD development, the effect of the NMDA antagonist, memantine (1-amino-3,5-dimethyladamantane), was studied in a rat model of TD. 2. In an acute experiment, six groups of rats were treated daily for 1 week with either vehicle or memantine 20 or 40 mg kg-1 day-1, and on the seventh day they received one injection of either haloperidol 1.0 mg kg-1 i.p. or saline i.p. In a subsequent long-term experiment lasting 20 weeks, the same treatment was continued, except that haloperidol was injected i.m. as decanoate (38 mg kg-1 every 4 weeks) and control rats received sesame oil. The behaviour was videotaped and scored at intervals during both experiments, and for 16 weeks after cessation of the long-term treatment. 3. In the acute experiment, haloperidol decreased motor activity and memantine increased moving and tended to attenuate the immobility induced by haloperidol. Memantine also enhanced the haloperidol-induced increase in the putative TD-analogue vacuous chewing movements (VCM). 4. In the long-term experiment, the most marked effect of haloperidol was a gradual increase in VCM and the increase persisted significantly for 12 weeks after cessation of treatment. Memantine dose-dependently increased VCM and moving during long-term treatment. However, only one week after stopping treatment, both these effects of memantine disappeared. In contrast to rats previously treated with haloperidol alone, rats co-treated with memantine (both doses) and haloperidol had VCM at the level of controls two weeks after stopping treatment. The blood levels of drugs were within the therapeutic range achieved in human subjects. 5. These results suggest that long-lasting changes induced by haloperidol are prevented by memantine, which supports the theory that excessive NMDA receptor stimulation may be a mechanism underlying the development of persistent VCM in rats and maybe also TD in human subjects.

GM1 ganglioside attenuates the development of vacuous chewing movements induced by long-term haloperidol treatment of rats.

Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if TD may be a result of neuroleptic-induced excessive stimulation of striatal glutamate receptors, the effect of the anti-excitotoxic GM1 ganglioside was studied in a rat model of TD. In an acute experiment each of four groups of rats was treated with GM1 20 mg/kg SC+saline IP, saline SC+haloperidol 1.2 mg/kg IP, GM1 SC+haloperidol IP, or saline SC+saline IP. In a subsequent long-term experiment lasting 16 weeks, each of the four groups was treated as in the acute experiment, with the exception that haloperidol was injected IM as decanoate 38 mg/kg every 4 weeks, and the controls received vehicle injections. The behavior was videotaped and scored at intervals during both experiments, including 16 weeks after cessation of the long-term treatment. Haloperidol induced a significant increase in vacuous chewing movements (VCM) and immobility both in the acute and in the long-term experiment. Other categories of behaviour (rearing, moving, sitting) were significantly affected only in the acute experiment. GM1 did not affect any of the acute behavioural effects of haloperidol, but significantly reduced VCM in the long-term experiment. The effects on VCM of haloperidol and GM1 persisted for at least 8 weeks after cessation of the long-term treatment. These results suggest that long-lasting changes in striatal function induced by excessive glutamate receptor stimulation may be a mechanism for the development of VCM in rats and perhaps also for TD in humans.

Tardive dyskinesia: Behavioral effects of repeated intracerebroventricular haloperidol injections in rats do not confirm the kindling hypothesis

The development of tardive dyskinesia (TD) has been claimed to be the result of a kindling-like mechanism. This hypothesis is based on studies suggesting that intermittent neuroleptic treatment may increase the risk of irreversible TD in humans and persistent vacuous chewing movements (VCM) in rats. We investigated the effect of daily intracerebroventricular (ICV) injections of haloperidol 37.5 μg/kg for 12 weeks in rats. Behavior was recorded immediately after the first injection, with 2 weeks intervals during treatment, and 3 weeks after drug withdrawal. In a separate experiment, rats received one injection of haloperidol IP. The acute effect of haloperidol ICV was an immediate increase in VCM and a reduction in motor activity that lasted for approximately 2 h. The behavioral response to haloperidol IP was similar, but of much longer duration. No significant behavioral changes were observed either 24 h after the ICV injections during haloperidol treatment or 3 weeks after drug withdrawal. The results did not support the hypothesis that kindling is important for the development of TD.

Increase in rat striatal extracellular dopamine and vacous chewing produced by two σ receptor ligands

The present studies were carried out to analyze the neurochemical and behavioral effects of peripheral σ ligand administration in the rat. Based upon previous studies which showed an increase in turning behavior following unilateral intranigral administration of σ ligands, we determined the effects of two σ ligands, 1,3-di-o-tolylguanidine (DTG) and (+)-pentazocine, on extracellular dopamine levels in the rat striatum. Dopamine levels were monitored via microdialysis in awake freely moving animals following i.p. injection of the ligands. Both DTG (1 and 3 mg/kg) and (+)-pentazocine (10 mg/kg) produced a significant (30–50%) increase in extracellular dopamine. Given the relatively high concentration of σ receptors in brain nuclei involved in facial and mouth movements, we have also determined the effects of the two σ ligands on facial movements. Both ligands produced a significant increase in vacuous chewing movements, suggesting that studies on the consequences of σ receptor activation may have relevance to animal models of human dystonia and/or dyskinesia.