Animal Model Of Tardive Dyskinesia Research Articles

A unifying theory for the pathoetiologic mechanism of tardive dyskinesia

IntroductionChronic treatment with dopamine D2 receptor antagonists has been proposed to lead to dopamine receptor supersensitivity. Frequently, this is conceptualized as upregulation or changes in the structure or function of the post-synaptic D2 receptor. However, the measured 1.4-fold increase in D2 receptor density and the lack of actual receptor supersensitivity are probably inadequate to explain outcomes such as tardive dyskinesia (TD) and dopamine supersensitivity psychosis. HypothesisRecent data suggest that TD may result from a combination of presynaptic, synaptic, and postsynaptic changes. DiscussionPresynaptic increase in dopamine release occurs when super-therapeutic blockade of postsynaptic D2 receptors results in excess synaptic unbound dopamine which ultimately ends up being reuptaken by the presynaptic neuron through the dopamine transporter. The increased availability of recycled dopamine results in higher vesicular dopamine concentrations. Since the quantity of neurotransmitter released (known as quanta) is determined by the number of presynaptic neurotransmitter vesicles, the increase in the number (concentration) of dopamine molecules in the vesicles results in a higher concentration of synaptic dopamine with successive depolarization events. Synaptic changes such as the appearance of perforated synapses which is an early step in new synapse formation have been shown in animal models of TD. Finally, postsynaptic increases in D2 receptor expression without demonstration of increased sensitivity or potency has been demonstrated. ConclusionTD likely develops due to changes across the synapse and terminology such as ‘dopamine receptor supersensitivity’ can be misleading. ‘Synaptic upregulation’ may be a more correct term.

Neurobiological Basis of Dyskinetic Effects Induced by Antipsychotics: the Contribution of Animal Models

Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications. Currently, there is no satisfactory pharmacotherapy for TD, which represents a major limitation to therapy with classical antipsychotics. In order to develop or optimize therapies for TD, and to develop new APDs with lower indices of motor side effects, the pathology underlying TD must first be understood. The use of animal models has been used to further this objective. Here, we review different preparations that have been used to model TD and discuss the contribution of neuroimaging studies conducted in these models. Studies in animal models have lead to several hypotheses of TD pathology, although none has yet emerged as the ultimate underlying cause of this syndrome. We discuss alterations in functional indices, neuron and synapse morphology and changes in specific neurotransmitter systems that have been described in animal models of TD, and outline how these findings have contributed to our understanding of antipsychotic-induced dyskinesias. We conclude that several non-mutually exclusive theories of TD are supported by animal studies, including increases in oxidative stress leading to structural and functional changes in specific neurotransmitter systems. Elucidating the mechanisms underlying TD neuropathology partly through the use of animal models will lead to the development of APDs with superior side effect profiles or more effective therapies for TD.

Reversal of reserpine-induced orofacial dyskinesia and catalepsy by Nardostachys jatamansi

Context:Reserpine-induced orofacial dyskinesia is an animal model of tardive dyskinesia which may be associated with neurodegeneration and free radical damage.Aim:The aim was to assess the neuroprotective potential and in vivo antioxidant status of alcoholic extract of roots and rhizomes of Nardostachys jatamansi (ANJ) and its triterpenes (TNJ) in reserpine-induced orofacial dyskinesia.Materials and Methods:In the present study, repeated treatment with reserpine (1.0 mg/kg) on each other day for a period of 5 days (days 1, 3, and 5) significantly induced vacuous chewing movements (VCMs) and tongue protrusions (TPs) in rats. The effect on reserpine-induced catalepsy was also studied. The effect of ANJ and TNJ on levels of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH) and inhibition of lipid peroxidation (LPO) in the forebrain region was assessed.Statistical Analysis:All observations were expressed as mean ± SEM. Statistical analysis was performed by the one-way ANOVA followed by Dunnett's test. P<0.05 was regarded as statistically significant.Results:At the end of the treatment schedule, ANJ and TNJ significantly inhibited reserpine-induced VCM, TP, and catalepsy, and significantly increased the locomotion and rearing in the open-field test. Treatment with ANJ and TNJ exhibited significant elevation in the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH) and inhibition of lipid peroxidation (LPO) in forebrain region compared to the reserpine treated group.Conclusions:The study concludes that ANJ and TNJ significantly protected animals against reserpine-induced orofacial dyskinesia as well as catalepsy suggesting its potential value in the treatment of neuroleptic-induced orofacial dyskinesia and Parkinson's disease.

Protective Effect of Leaves of Murraya koenigii on Reserpine-Induced Orofacial Dyskinesia.

Murraya koenigii L. (Rutaceae), commonly known as curry leaf tree, closely associated with south India where the word "curry" originates from the Tamil "kari" for spiced sauces. Curry leaves are a rich source of carbazole alkaloids which possess various biological activities such as antitumor, antioxidant and anti-inflammatory. Curry leaf has a potential role in the treatment of diabetes. Reserpine-induced orofacial dyskinesia in rats is an animal model of tardive dyskinesia that has been linked with free radical generation and oxidative stress. In this study, neuroprotective potential and in-vivo antioxidant status of methanol extract of the leaves of Murraya koenigii (MEMK) in reserpine-induced orofacial dyskinesia are investigated. Reserpine was used to induce orofacial dyskinesia. The effect of MEMK on locomotion and catalepsy was studied using Open-field apparatus and Bar-test, respectively. The effect of MEMK on the levels of protective anti-oxidant enzymes i.e. superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH) and inhibited lipid peroxidation (LPO) in forebrain region were investigated in reserpine-treated animals. Results demonstrated that the MEMK significantly inhibited the reserpine-induced vacuous chewing movements (VCM), tongue protrusion (TP), orofacial burst (OB) and catalepsy. MEMK significantly increased the number of squares traversed and rearing in open field apparatus. Treatment with MEMK significantly restored the levels of protective anti-oxidant enzymes i.e. SOD, CAT, GSH and inhibited LPO in forebrain region when compared with reserpine. It also inhibited haloperidol-induced catalepsy. The present study concludes that the oxidative stress might play an important role in reserpine-induced abnormal oral movements, and Murraya koenigii may have great potential in the treatment of neuroleptic-induced orofacial dyskinesia.

Alpha-phenyl- N-tert-butylnitrone prevents oxidative stress in a haloperidol-induced animal model of tardive dyskinesia: Investigating the behavioural and biochemical changes

Haloperidol (HP) is a widely prescribed antipsychotic drug used for the treatment of mental disorders. However, while providing therapeutic benefits, this drug also causes serious extrapyramidal side effects, such as tardive dyskinesia (TD). Upon chronic administration, HP causes behavioural supersensitivity to dopamine D2 receptor agonists, as well as the development of vacuous chewing movements (VCMs), in an animal model of human TD. Currently, a prevailing hypothesis to account for these behavioural abnormalities implicates oxidative stress. This study was undertaken to examine whether the free radical trapping agent, α-phenyl- N-tert-butylnitrone (PBN), can prevent the development of behavioural supersensitivity to dopamine D2 receptor agonists and the development of VCMs. Additionally, the study examined whether increased synthesis of apoptosis inducing factor (AIF) can result from HP-induced oxidative stress. Male Sprague–Dawley rats were treated with HP in conjunction with PBN, or its vehicle, for 4 weeks. After a 24-hour washout period, behavioural observations were recorded along with the estimation of lipid peroxidation and antioxidant enzyme activities. The free radical trapping agent, PBN, prevented the development of behavioural supersensitivity, reduced lipid peroxidation and prevented the reduction of antioxidant enzyme activities. AIF concentrations at the mRNA and protein levels remained unchanged; therefore increased AIF gene expression is unlikely to be involved in HP-induced oxidative stress. The findings of the present study suggest the involvement of striatal free radicals in the development of behavioural supersensitivity, and free radical trapping agents, such as PBN, as possible options for the treatment of extrapyramidal side effects in humans.

Dopamine receptor changes after long-term haloperidol treatment in rats.

Abstract Tardive dyskinesia is a neurological syndrome associated with prolonged neuroleptic treatment of schizophrenic patients (Crane 1968; Faurbye 1970; Faurbye et al 1964). It has been suggested that tardive dyskinesia results from chemical denervation of central dopamine neurons and subsequent development of supersensitivity of the postsynaptic receptor (Rubovits &amp; Klawans 1972). Experiments based on animal models of tardive dyskinesia support this hypothesis. Chronic neuroleptic treatment increases postsynaptic dopamine receptor sensitivity when measured either behaviourally or biochemically (Christensen et al 1976; Klawans &amp; Rubovits 1972; Moore &amp; Thornburg 1975; Sayers et al 1975; Tarsy &amp; Baldessarini 1974; Von Voigtlander et al 1975). The molecular basis for this behavioural change has been reported to be an increase in the number of receptor sites with no change in their affinity as measured by 3H-neuroleptic binding to striatal membrane homogenates (Burt et al 1977; Klawans et al 1977; Muller &amp; Seeman 1977). Previous biochemical reports of the development of model tardive dyskinesia after neuroleptic treatment of animals have generally used treatment periods of 3 weeks or less (Burt et al 1977; Klawans et al 1977; Muller &amp; Seeman 1977). Only one report treated animals for longer periods (Clow et al 1978). In the present experiments we studied the kinetics of [3H]spiroperidol binding to rat caudate nucleus homogenates after 3 and 10 weeks of haloperidol treatment.

Korean ginseng extract attenuates reserpine-induced orofacial dyskinesia and improves cognitive dysfunction in rats

Reserpine-induced orofacial dyskinesia in rats is an animal model of tardive dyskinesia that has been linked with free radical generation and oxidative stress. In the present study, reserpine (1 mg kg−1, s.c.) was given to rats on days 1, 3 and 5 to induce orofacial dyskinesia, which is characterised by increased vacuous chewing and tongue protrusion. Sub-chronic treatment with Korean ginseng extract from day 1 to day 21 along with reserpine on days 1, 3 and 5 significantly and dose-dependently (100 and 200 mg kg−1) reduced reserpine-induced vacuous chewing movements and tongue protrusions. Reserpine-treated animals also showed poor retention of memory in the elevated plus maze paradigm. The sub-chronic Korean ginseng extract administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that repeated reserpine treatment significantly induced lipid peroxidation and decreased glutathione (GSH) levels in the brains of rats. Reserpine-treated rats also showed decreased levels of antioxidant defence enzymes, superoxide dismutase (SOD), and catalase. Sub-chronic administration of Korean ginseng extract dose-dependently and significantly reduced lipid peroxidation and restored decreased GSH levels by repeated reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The present study concludes that oxidative stress might play an important role in reserpine-induced abnormal oral movements, and Korean ginseng extract could be useful in the treatment of drug-induced dyskinesia and amnesia.

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.

Differential striatal levels of TNF-α, NFκB p65 subunit and dopamine with chronic typical and atypical neuroleptic treatment: Role in orofacial dyskinesia

Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-α and NFκB on the toxicity induced by chronic haloperidol administration in an animal model of tardive dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-α and NFκB p65 subunit were measured by ELISA technique. Haloperidol increased orofacial dyskinetic movements and total locomotor activity (on day 22) ( P ≤ 0.05). Clozapine and risperidone also increased the orofacial dyskinetic movements but that significantly less than haloperidol ( P ≤ 0.05). Differential effect of haloperidol and atypical neuroleptics on striatal dopamine levels and striatal levels of TNF-α and NFκB p65 subunit was found out. Haloperidol significantly decreased the striatal dopamine levels whereas clozapine and risperidone did not. Haloperidol but not clozapine and risperidone significantly increased the levels of TNF-α and NFκB p65 subunit ( P ≤ 0.05). The present study suggests the impossible involvement of striatal TNF-α and NFκB p65 subunit in haloperidol-induced orofacial dyskinesia in rats, an animal model for human tardive dyskinesia.

Increase in the effectiveness of somatodendritic 5-HT-1A receptors in a rat model of tardive dyskinesia

The present study concerns responsiveness of pre- and postsynaptic 5-hydroxytryptamine (5-HT)-1A receptors in a rat model of tardive dyskinesia (TD). Vacuous chewing movements (VCMs) in rats are widely accepted as an animal model of TD. Results show that haloperidol injected at a dose of 1 mg/kg twice a day for 5 weeks elicited VCMs, which increased in a time dependent manner following the drug administration for 3Ė5 weeks. Tolerance was produced in motor coordination during the potentiation of VCMs. Exploratory activity in an open field and in an activity box decreased in haloperidol treated animals. The effects of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 0.5 mg/kg) were monitored 48-h after withdrawal from repeated administration of haloperidol. 8-OH-DPAT-induced locomotion was greater in haloperidol treated rats. 5-HT synthesis increased in haloperidol treated animals, while 8-OH-DPAT-induced decreases of 5-HT synthesis were greater in repeated haloperidol than repeated saline injected animals. The results suggest that an increase in the effectiveness of somatodendritic 5-HT-1A receptors may decrease the inhibitory influence of 5-HT on the activity of dopaminergic neurons to precipitate VCMs. The 5-HT-1A agonist may help to alleviate neuroleptic-induced TD.

Progesterone attenuates neuroleptic-induced orofacial dyskinesia via the activity of its metabolite, allopregnanolone, a positive GABA A modulating neurosteroid

GABAergic hypofunction in the basal ganglia is stated as an important mechanism underlying the pathophysiology of tardive dyskinesia. In the present study we sought to establish the protective effect of progesterone in haloperidol-induced orofacial dyskinesia. Besides this we also tried to find out whether the GABA A facilitatory action of progesterone metabolites is responsible for the action of progesterone in attenuating the haloperidol-induced orofacial dyskinesia, an animal model of tardive dyskinesia. Chronic administration of haloperidol (1 mg/kg, i.p. 21 days) induced significant increase in hyperkinetic orofacial dyskinetic movements and oxidative damage in the brain as compared to control group. Coadministration of progesterone (5–20 mg/kg, i.p. 21 days) dose dependently prevented the hyperkinetic orofacial movements as well as oxidative damage parameters. The protective activity of progesterone was reversed by pre treatment with finasteride (50 mg/kg i.p.), a 5α-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone and other metabolites. Further, chronic administration of haloperidol resulted in significant decrease in dopamine levels in rat striatum homogenates and increase in catecholamine metabolite levels. Coadministration of progesterone also reversed the decrease in dopamine levels induced by chronic haloperidol treatment, an effect which was again reversed by pre treatment with finasteride. Our study provides strong evidence that the protective effect of progesterone resides in the GABAergic as well as neuroprotective activity of its metabolite allopregnanolone. These findings lend support to recognized GABA hypofunction theory of tardive dyskinesia and strongly suggest progesterone as a protective therapy in this debilitating movement disorder.

Possible anti-oxidant and neuroprotective mechanisms of zolpidem in attenuating typical anti-psychotic-induced orofacial dyskinesia—A biochemical and neurochemical study

Tardive dyskinesia is a serious motor side effect of chronic anti-psychotic therapy. The pathophysiology of this disabling and commonly irreversible movement disorder continues obscure and may be caused due to GABAergic hypofunction or increased oxidative damage and free radical generation. Chronic treatment with typical antipsychotics leads to the development of abnormal hyperkinetic orofacial movements (vacuous chewing movements, tongue protrusions and facial jerking) in rats and is widely accepted as the animal model for tardive dyskinesia. Zolpidem, a GABA-mimetic drug is structurally related to melatonin and has been reported to possess anti-oxidant and neuroprotective effects both in vivo and in vitro. The study was carried out to investigate whether zolpidem can be used in the treatment of typical anti-psychotic-induced orofacial dyskinesia. Chronic haloperidol (1 mg/kg, i.p. for 21 days) and chlorpromazine (5 mg/kg, i.p. for 21 days) treatment significantly induced orofacial hyperkinetic movements and zolpidem [ N, N, 6-trimethyl-2- p-tolyl-imidazo (1, 2- a) pyridine 3-acetamideL-(+)] dose dependently (1, 2, 5 mg/kg i.p. for 21 days) reduced these haloperidol and chlorpromazine-induced hyperkinetic orofacial movements. Biochemical analysis revealed that haloperidol and chlorpromazine treatment significantly induced increase in lipid peroxidation and decrease in the levels of total nitric oxide levels, non-protein thiols (NPSH) and of anti-oxidant defense enzymes, superoxide dismutase (SOD) and catalase in the striatum of rat brain. Co-administration of zolpidem (1, 2, 5 mg/kg i.p. for 21 days) significantly reduced the lipid peroxidation and restored the non-protein thiols and total nitric oxide levels induced by chronic haloperidol and chlorpromazine treatment. It also significantly reversed the haloperidol and chlorpromazine-induced decrease in brain SOD and catalase activity. Neurochemical analysis (Neurotransmitter and their metabolite level estimation) revealed that haloperidol and chlorpromazine significantly decreased the dopamine, norepinephrine and serotonin levels in brain homogenates where as it caused a significant increase in the metabolite (VMA and HVA) levels in urine, which were significantly reversed by zolpidem at higher doses. Result of the present study support the therapeutic use of zolpidem in the treatment of typical anti-psychotic-induced orofacial dyskinesia.

Reversal of haloperidol-induced tardive vacuous chewing movements and supersensitive somatodendritic serotonergic response by buspirone in rats

Tardive dyskinesia (TD), a syndrome of involuntary hyperkinesias in the orofacial region that develops in patients chronically treated with neuroleptic agents is a major limitation of the therapy. Rats chronically treated with haloperidol exhibit vacuous chewing movements (VCMs) with the twitching of facial musculature and tongue protrusion. The syndrome is widely used as an animal model of TD. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the pathogenesis and treatment of TD because repeated administration of haloperidol resulted in an increase in the effectiveness of 5-HT-1A receptors while drugs with agonist activity at 5-HT-1A receptors could attenuate haloperidol-induced VCMs. The present study was designed to test the hypothesis that a decrease in the responsiveness of somatodendritic 5-HT-1A receptors by the coadministration of buspirone could reverse the induction of VCMs and supersensitivity at 5-HT-1A receptors by haloperidol. Rats treated with haloperidol at a dose of 1 mg/kg twice a day for 2 weeks displayed VCMs with twitching of facial musculature that increased in a time dependent manner as the treatment continued to 5 weeks. Coadministration of buspirone attenuated haloperidol-induced VCMs after 2 weeks and completely prevented it after 5 weeks. The intensity of 8-hydroxy-2-di ( n-propylamino) tetralin (8-OH-DPAT)-induced locomotion was greater in saline + haloperidol injected animals but not in buspirone + haloperidol injected animals. 8-OH-DPAT-induced decreases of 5-HT metabolism were greater in saline + haloperidol injected animals but not in buspirone + haloperidol injected animals. It is suggested that an impaired somatodendritic 5-HT-1A receptor dependent response is a major contributing factor in the pathophysiology of TD and a normalization of the somatodendritic response by drugs may help extending therapeutics in schizophrenia.

Protective Effect of Adenosine Reuptake Inhibitors in Haloperidol-Induced Orofacial Dyskinesia and Associated Behavioural, Biochemical and Neurochemical Changes

Chronic administration of typical neuroleptics is known to cause persistent oral dyskinesia in rats, an alleged animal model of tardive dyskinesia (TD). The pathophysiology of the syndrome remains unclear. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides γ-aminobutyric acid. Based on the hypothesis that adenosinergic receptor system may involve in the pathogenesis of TD, we investigated the effect of dipyridamole (5 and 10 mg/kg, i.p.), an adenosine reuptake inhibitor and nimodipine (10 and 20 mg/kg, i.p.) an adenosine transport inhibitor in haloperidol-induced TD by using different behavioural, biochemical and neurochemical parameters in rats. Chronic administration of haloperidol (1 mg/kg, i.p., for 21 days) significantly increased vacuous chewing movements, tongue protrusion, facial jerking which was prevented by adenosine reuptake inhibitors. Chronic administration of haloperidol also resulted in the development of dopamine sensitivity as suggested by increased locomotor activity and stereotypy and decreased % retention time on elevated plus maze paradigm. Pretreatment with adenosine reuptake/transport inhibitors, dipyridamole and nimodipine prevented all these behavioural changes. Chronic administration of haloperidol also resulted in increased oxidative damage in all brain regions which was prevented dose-dependently by both dipyridamole and nimodipine in different brain regions. Chronic administration of haloperidol resulted in decreased turnover of dopamine and norepinephrine in both cortex and subcortical regions which was dose-dependently prevented by adenosine reuptake/transport inhibitors. The major findings of the present study suggested that adenosine reuptake inhibitors dipyridamole and nimodipine could be a possible therapeutic option in neuroleptic induced TD.

Modeling tardive dyskinesia: Predictive 5-HT2C receptor antagonist treatment

Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D(2) receptor blockers. Also, acute DA D(1) agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D(1) receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA) -induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D(1) induction of VCMs. Moreover, in 6-OHDA-lesioned rats treated with haloperidol for one year, there a 2-fold increase in numbers of VCMs (vs intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT(2) receptor antagonists, but not DA D(1) receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT(2) receptor antagonists, more specifically 5-HT(2C) receptor antagonists, as a rational treatment approach for TD in humans.

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.

Involvement of adenosinergic receptor system in an animal model of tardive dyskinesia and associated behavioural, biochemical and neurochemical changes

Tardive dyskinesia is a syndrome characterized by repetitive involuntary movements usually involving the mouth, face and tongue. It is considered as the late onset adverse effect of prolonged administration of typical neuroleptic drugs. Adenosine is now widely accepted as the major inhibitory neuromodulators in the central nervous system besides GABA. Both, agonists of adenosine A 1 and A 2 receptors and the antagonists of A 2A receptors are known to protect against neuronal damage caused by toxins as well as they can also protect against the cell damage inflicted by reactive oxygen species. The present study investigated the effect of adenosine and A 2A receptor antagonist, caffeine in an animal model of tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypic rearing, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (superoxide dismutase and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, facial jerking in rats which was dose dependently inhibited by adenosine and caffeine. Chronic administration of haloperidol also resulted in an increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypic rearing after day 14. Chronic administration of haloperidol also decreased % retention time on elevated plus maze paradigm. Treatment with adenosine or caffeine reversed these behavioural changes. Besides, haloperidol also induced oxidative damage in all regions of brain which was prevented by caffeine and adenosine, especially in striatum. On chronic administration of haloperidol there was a decrease in dopamine and norepinephrine turnover which was dose-dependently reversed by treatment with adenosine or caffeine. When caffeine and adenosine were co-administered, there was no synergistic effect, possibly due to mutual antagonistic effects. The findings of the present study suggested the involvement of adenosinergic receptor system in the genesis of neuroleptic-induced tardive dyskinesia.

Effect of Withania somnifera root extract on reserpine‐induced orofacial dyskinesia and cognitive dysfunction

Tardive dyskinesia is one of the major side effects of long-term neuroleptic treatment. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Oxidative stress and products of lipid peroxidation are implicated in the pathophysiology of tardive dyskinesia. Repeated treatment with reserpine (1.0 mg/kg) on alternate days for a period of 5 days (days 1, 3 and 5) significantly induced vacuous chewing movements and tongue protrusions in rats. Chronic treatment with Withania somnifera root extract (Ws) for a period of 4 weeks to reserpine treated animals significantly and dose dependently (50 and 100 mg/kg) reduced the reserpine-induced vacuous chewing movements and tongue protrusions. Reserpine treated animals also showed poor retention of memory in the elevated plus maze task paradigm. Chronic Ws administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that chronic reserpine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the brains of rats. Chronic reserpine treated rats showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Chronic administration of Ws root extract dose dependently (50 and 100 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased glutathione levels by chronic reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The major findings of the present study indicate that oxidative stress might play an important role in the pathophysiology of reserpine-induced abnormal oral movements. In conclusion, Withania somnifera root extract could be a useful drug for the treatment of drug-induced dyskinesia.

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.

High fat diet increases the incidence of orofacial dyskinesia and oxidative stress in specific brain regions of rats

Haloperidol-induced orofacial dyskinesia (OD) is a putative animal model of tardive dyskinesia (TD) whose pathophysiology has been related to free radical generation and oxidative stress. Schizophrenic patients have been reported to eat a diet higher in fat than the general population and dietary fat intake can lead to an increase in oxidative stress in animal models. The objective of this study was to determine whether association of ingestion of a high fat diet with prolonged haloperidol treatment could lead to OD and oxidative stress in the rat brain. Haloperidol decanoate administration (38 mg/kg, IM, which is equivalent to 1 mg/kg/day) monthly for a period of 6 months to rats fed previously with a high fat and normo fat diets (6 months) caused a increase in vacuous chewing (VCM) and duration of facial twitching (FT). Haloperidol caused a reduction in body weight gain and the loss of body weight occurred after 4 months of treatment with haloperidol. The effects on body weight were more accentuated in HF diet group. HF diet ingestion was associated with an increase in TBARS levels in cerebellum and cerebral cortex (regardless of haloperidol treatment). A significant diet × haloperidol treatment interaction in striatum, subcortical parts and the region containing the substantia nigra was observed for TBARS. In fact, haloperidol caused an increase in TBARS levels of these regions only in rats fed with the HF. These results indicate that a high fat diet caused a transitory increase in haloperidol-induced OD in rats and this in part can be related to the haloperidol-induced oxidative stress in brain structures involved with OD.