Protective effect of Curcumin, the active principle of turmeric (Curcuma longa) in haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes in rat brain

Tardive dyskinesia (TD) is a motor disorder of the orofacial region resulting from chronic neuroleptic treatment. A high incidence and irreversibility of this hyperkinetic disorder has been considered a major clinical issue in the treatment of schizophrenia. The molecular mechanism related to the pathophysiology of tardive dyskinesia is not completely known. Various animal studies have demonstrated an enhanced oxidative stress and increased glutamatergic transmission as well as inhibition in the glutamate uptake after the chronic administration of haloperidol. The present study investigated the effect of curcumin, an antioxidant, in haloperidol-induced tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCM's), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by curcumin. Chronic administration of haloperidol also resulted in increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypy and also decreased % retention time on elevated plus maze paradigm. Pretreatment with curcumin reversed these behavioral changes. Besides, haloperidol also induced oxidative damage in all major regions of brain which was attenuated by curcumin, especially in the subcortical region containing striatum. On chronic administration of haloperidol, there was a decrease in turnover of dopamine, serotonin and norepinephrine in both cortical and subcortical regions which was again dose-dependently reversed by treatment with curcumin. The findings of the present study suggested for the involvement of free radicals in the development of neuroleptic-induced tardive dyskinesia and point to curcumin as a possible therapeutic option to treat this hyperkinetic movement disorder.     

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.     

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 gamma-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.     

Reversal of haloperidol-induced orofacial dyskinesia by quercetin,a bioflavonoid

Rationale. Tardive dyskinesia is a serious neurological syndrome associate with long-term administration of neuroleptics to humans and experimental animals. It may be caused by loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. Quercetin is a bioflavonoid with strong antioxidant properties. Objectives. To evaluate the effect of chronic quercetin treatment on haloperidol-induced orofacial dyskinesia. Methods. Vacuous chewing movements (VCM) in rats, a widely accepted animal model of tardive dyskinesia was employed in the present study. VCM were induced in rats by daily administration of haloperidol (1.0 mg/kg) for a period of 21 days. Animals with established dyskinesia were given quercetin for a period of 4 weeks and behavioral scoring was recorded every week before administration of quercetin. Animals were killed after the last behavioral recordings and biochemical estimations were carried out. Results. Chronic haloperidol (1.0 mg/kg for 21 days) treatment significantly induced VCM and tongue protrusions in rats and quercetin (25–100 mg/kg for 4 weeks) significantly reversed haloperidol-induced VCM and tongue protrusions. Biochemical analysis revealed that chronic haloperidol treatment significantly induced lipid peroxidation, decreased glutathione (GSH), superoxide dismutase (SOD), and catalase levels in the brains of rats. Quercetin (25–100 mg/kg for 4 weeks) significantly reduced lipid peroxidation and restored GSH, SOD and catalase levels. Conclusions. The results of the present study clearly indicate that quercetin has a protective role against haloperidol-induced orofacial dyskinesia. Consequently, the use of quercetin as a therapeutic agent for the treatment of tardive dyskinesia should be considered. Electronic Publication     

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.     

Possible mechanism of action in melatonin attenuation of haloperidol-induced orofacial dyskinesia

Tardive dyskinesia (TD) is a late complication of prolonged neuroleptic treatment characterized by involuntary movements of the oral region. In spite of high incidence and much research, the pathophysiology of this devastating movement disorder remains elusive. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats, referred to as vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of TD. Rats chronically treated with haloperidol (1.5 mg/kg ip) significantly developed VCMs and tongue protrusions. Melatonin dose-dependently (1, 2, and 5 mg/kg) reversed the haloperidol-induced VCM and tongue protrusions frequencies. Biochemical analysis reveals that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the forebrain glutathione (GSH) levels in the rats. Chronic haloperidol-treated rats also showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Coadministration of melatonin (1, 2, and 5 mg/kg) along with haloperidol significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic haloperidol treatment, and significantly reversed the haloperidol-induced decrease in forebrain SOD and catalase levels in rats. However, a lower dose of melatonin (1 mg/kg) failed to reverse chronic haloperidol-induced decreases in forebrain GSH, SOD, and catalase levels. In conclusion, melatonin could be screened as a potential drug candidate for the prevention or treatment of neuroleptic-induced orofacial dyskinesia.     

Co-administration of nitric oxide (NO) donors prevents haloperidol-induced orofacial dyskinesia, oxidative damage and change in striatal dopamine levels

Tardive dyskinesia (TD) has been considered as a major clinical issue in the treatment of schizophrenia. Various animal studies have indicated the role of oxidative stress and nitric oxide pathway in haloperidol-induced TD. The present study investigated the effect of NO donors (molsidomine and l-arginine) in haloperidol-induced TD in rats. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCMs), tongue protrusions, and facial jerking in rats which was dose dependently inhibited by NO donors. Besides, haloperidol also increased striatal superoxide anion levels and decreased striatal NO and citrulline levels which were prevented by molsidomine and l-arginine. On chronic administration of haloperidol, there was a decrease in the striatal levels of dopamine, which was again reversed by treatment with NO donors. The findings of the present study suggested for the involvement of NO in the development of neuroleptic-induced TD and indicated the potential of NO donors as a possible therapeutic option. Furthermore, a sub-study on a possible schizophrenic phenotype, i.e. a possible clinical worsening in the animals receiving NO donors and neuroleptics will substantiate the clinical utility of the study.     

Neurochemical changes associated with chronic administration of typical antipsychotics and its relationship with tardive dyskinesia

The therapeutic success of atypical antipsychotics has focused the attention on the role of receptor systems other than dopaminergic system in the pathophysiology of neuroleptic-associated extrapyramidal side effects such as tardive dyskinesia. In the present study we planned to study time-dependent changes in extracellular levels of norepinephrine, dopamine and serotonin in cortical and subcortical (including striatum) regions of brain and tried to correlate them with hyperkinetic motor activities (vacuous chewing movements [VCMs], tongue protrusions and facial jerking) in rats treated chronically with typical neuroleptics (haloperidol and chlorpromazine). Chronic administration of haloperidol (1 mg/kg) and chlorpromazine (5 mg/kg) resulted in a time-dependent increase in orofacial hyperkinetic movements. There were also significant changes in the extracellular levels of different neurotransmitters in different brain regions (cortical and subcortical regions) as measured by high-performance liquid chromatography/electrochemical detection (HPLC/ED). Both haloperidol and chlorpromazine produced time-dependent decreases in the levels of these neurotransmitters.     

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

Rationale 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. Objective 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. Materials and methods 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. Conclusions 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.     

Reversal of reserpine-induced orofacial dyskinesia and cognitive dysfunction by quercetin

Tardive dyskinesia (TD) is a serious neurological syndrome associated with long-term administration of neuroleptics to humans and experimental animals. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells or may be due to free radicals as a product of high synaptic dopamine levels. Quercetin is a bioflavonoid with strong antioxidant properties. 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. Chronic treatment with quercetin for a period of 4 weeks to reserpine-treated animals significantly and dose dependently (50 and 100 mg/kg) reduced the reserpine-induced VCMs and TPs. Reserpine-treated animals also showed poor retention of memory in elevated plus-maze task paradigm. Chronic quercetin 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 quercetin dose dependently (50-100 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The results of the present study clearly indicated that quercetin has a protective role against reserpine-induced orofacial dyskinesia and memory impairment. Consequently, the use of quercetin as a therapeutic agent for the treatment of TD should be considered.     

Molindone compared to haloperidol in a guinea-pig model of tardive dyskinesia

Molindone was compared with haloperidol in animal models of tardive dyskinesia. Treatment with molindone for 14 days at 3, 6, 20 and 40 mg/kg, enhanced the stereotyped behavioral response induced by apomorphine and increased the number of D-2 dopamine receptors in the striatum (B_max) labelled by high affinity (K_d = 40 pmol) binding or [³H]spiroperidol in the guinea-pig. Molindone at 1 mg/kg, caused no behavioral supersensitivity or change in the binding of dopamine receptors. Chronic administration of haloperidol (0.1, 0.5 and 5.0 mg/kg) also increased both the behavioral response to apomorphine and the number of dopamine receptors. Haloperidol, at 0.02 and 0.004 mg/kg, had no effect. Molindone potentiated dopaminergic activity in animal models in a similar way to other neuroleptics, suggesting that its use may also result in tardive dyskinesia.     

Behavioral aspects of serotonin-dopamine interaction in the monkey

The effects of serotonin (5-hydroxytryptamine; 5-HT) antagonists and 5-HT uptake inhibitors on the behavioral response to amphetamine and haloperidol in monkeys (cercopithecus aethiops) were investigated. Amphetamine increased locomotor activity and reactivity and induced repetitive movements of head, limbs and trunk, but no oral hyperkinesia. Haloperidol induced dystonia and parkinsonism. Pretreatment with the 5-HT antagonists cyproheptadine and mianserin increased amphetamine-induced locomotor activity, reactivity and repetitive movements and decreased haloperidol-induced dystonia and parkinsonism. Conversely the 5-HT uptake inhibitors paroxetine and CGP 6085 A decreased amphetamine-induced repetitive movements and aggravated haloperidol-induced dystonia and parkinsonism. The 5-HT uptake inhibitors produced oral hyperkinesia resembling human tardive dyskinesia, which was intensified by amphetamine and blocked by haloperidol. These findings support the suggestion that 5-HT inhibits dopamine functions and may imply that 5-HT antagonists could have a beneficial effect against acute extrapyramidal side-effects of neuroleptic treatment. 5-HT uptake inhibitors in the monkey may serve as a model for tardive dyskinesia.     

Possible antioxidant and neuroprotective mechanisms of FK506 in attenuating haloperidol-induced orofacial dyskinesia

Tardive dyskinesia is a serious motor side effect of chronic neuroleptic therapy. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Chronic haloperidol (1 mg/kg for 21 days) treatment significantly induced vacuous chewing movements and tongue protrusions in rats, and FK506 (Tacrolimus) [[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14, 16-dimethoxy-4,10,12, 18-tetramethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate] dose dependently (0.5 and 1 mg/kg) reduced these haloperidol-induced movements. Biochemical analysis revealed that chronic haloperidol treatment significantly induced lipid peroxidation and decreased the levels of glutathione and of the antioxidant defense enzymes, superoxide dismutase and catalase, in the brains of rats. Co-administration of FK506 dose dependently (0.5 and 1 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased glutathione levels induced by chronic haloperidol treatment. It also significantly reversed the haloperidol-induced decrease in brain superoxide dismutase and catalase levels. The major findings of the present study suggest that oxidative stress-induced neuronal death might play a significant role in neuroleptic-induced orofacial dyskinesia. In conclusion, FK506 could be a useful drug for the treatment of neuroleptic-induced orofacial dyskinesia.     

Carvedilol attenuates neuroleptic-induced orofacial dyskinesia: possible antioxidant mechanisms

1. Tardive dyskinesia (TD), a syndrome of potentially irreversible, involuntary hyperkinetic disorder occurring in 20 - 40% of the patient population undergoing chronic neuroleptic treatment is a major limitation of neuroleptic therapy. 2. Oxidative stress and products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia. 3. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. 4. All the antipsychotics were administered i.p. once daily for 21 days, whereas carvedilol (also i.p.) was administered twice daily. Rats chronically treated with haloperidol (1.0 mg kg(-1)) or chlorpromazine (5 mg kg(-1)) but not clozapine (2 mg kg(-1)) significantly developed vacuous chewing movements and tongue protrusions. Carvedilol dose dependently (0.5 - 2 mg kg(-1)) reduced the haloperidol or chlorpromazine-induced vacuous chewing movements and tongue protrusions. 5. Biochemical analysis revealed that chronic haloperidol or chlorpromazine but not clozapine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the forebrains of rats. Chronic haloperidol or chlorpromazine but not clozapine treated rats showed decreased forebrain levels of antioxidant defence enzymes, superoxide dismutase (SOD) and catalase. 6. Co-administration of carvedilol (0.5-2 mg kg(-1)) significantly reduced the lipid peroxidation and restored the decreased glutathione levels by chronic haloperidol or chlorpromazine treatment. Co-administration of carvedilol (1-2 mg kg(-1)) significantly reversed the haloperidol or chlorpromazine-induced decrease in forebrain SOD and catalase levels in rats. However, lower dose of carvedilol (0.5 mg kg(-1)) failed to reverse chronic haloperidol or chlorpromazine-induced decrease in forebrain SOD and catalase levels. 7. The major findings of the present study suggest that oxidative stress might play a significant role in neuroleptic-induced orofacial dyskinesia. In conclusion, carvedilol could be a useful drug for the treatment of neuroleptic-induced orofacial dyskinesia.     

Quercetin,a bioflavonoid,attenuates haloperidol-induced orofacial dyskinesia

Chronic treatment with neuroleptics leads to the development of abnormal orofacial movements described as vacuous chewing movements (VCMs) in rats. Vacuous chewing movements in rodents are widely accepted as one of the animal models of tardive dyskinesia. Oxidative stress and the products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia. In the present study chronic haloperidol (1.0 mg kg⁻¹ for 21 days) treatment induced vacuous chewing movements and tongue protrusions in rats. Co-administration of quercetin, a bioflavonoid, dose dependently (25–100 mg kg⁻¹) reduced haloperidol-induced vacuous chewing movements and tongue protrusions. Biochemical analysis revealed that chronic haloperidol treatment induces lipid peroxidation and decreases the glutathione (GSH) levels in the forebrains of rats. The antioxidant defense enzymes, superoxide dismutase (SOD) and catalase were also decreased due to chronic haloperidol treatment. Co-administration of quercetin (25–100 mg kg⁻¹) significantly reduced the lipid peroxidation and restored the decreased glutathione levels in these animals. Further quercetin (50–100 mg kg⁻¹) also reversed the haloperidol-induced decrease in forebrain SOD and catalase levels in rats. The major findings of the present study suggested that oxidative stress plays a significant role in neuroleptic-induced orofacial dyskinesia and quercetin co-administration reverses these behavioral and biochemical changes. Quercetin, a naturally occurring bioflavonoid could prove to be a useful agent in neuroleptic-induced orofacial dyskinesia.     

Reversal of haloperidol-induced orofacial dyskinesia by Murraya koenigii leaves in experimental animals

Context: Orofacial dyskinesia (OD) is a late complication of prolonged neuroleptic treatment characterized by involuntary movements of the oral region. Chronic treatment with neuroleptics leads to development of vacuous chewing movements (VCMs). VCMs in rats are widely accepted as an animal model of OD.

Objective: To study the effect of Murraya koenigii L. (Rutaceae) leaves on haloperidol-induced OD.

Materials and methods: Effect of alcohol extract of M. koenigii leaves (EEMK) and its alkaloid fraction (AMK) on body weight, locomotor activity, behavioral parameters, such as VCMs, tongue protrusions (TPs), orofacial bursts (OBs), and biochemical parameters such as antioxidant defense enzymes levels [superoxide dismutase (SOD) and catalase (CAT)], glutathione (GSH) levels, and lipid peroxidation (LPO) in the forebrain region was studied in haloperidol-treated rats.

Results: Rats chronically treated with haloperidol (1?mg/kg, i.p., 21 days) significantly decreased locomotion and developed VCMs, OBs, and TPs. Biochemical analysis reveals that chronic haloperidol-treated rats also showed decreased levels of SOD and CAT. Chronic haloperidol treatment significantly induced LPO and decreased the forebrain GSH levels in the rats. Co-administration of EEMK (100 and 300?mg/kg, p.o.) and AMK (30 and 100?mg/kg, p.o.) along with haloperidol significantly reversed the effect on locomotion. EEMK and AMK significantly reversed the haloperidol-induced decrease in forebrain SOD and CAT levels in rats and significantly reduced the LPO and restored the decreased GSH levels by chronic haloperidol treatment.

Conclusion: The study concludes that M. koenigii could be screened as a potential drug for the prevention or treatment of neuroleptic-induced OD.     

Possible involvement of prostaglandins in haloperidol-induced orofacial dyskinesia in rats

Dopaminergic abnormality is one of the pathological mechanisms involved in the pathophysiology of tardive dyskinesia, a late complication of neuroleptic treatment. Prostaglandins modulate the dopamine release in the striatum, the principle area involved in the pathophysiology of tardive dyskinesia. Rats were chronically treated with haloperidol (HPD) (1.5 mg/kg) for a period of 21 days, to induce orofacial dyskinesia. Behavioural assessment of orofacial dyskinesia was done 24 h after the last dose of haloperidol. Catalepsy was induced in rats by acute treatment with haloperidol (1 mg/kg), and catalepsy was scored for the next 4 h. Chronic haloperidol treatment induced profound vacuous chewing movements in rats. Indomethacin, a nonselective cyclooxygenase inhibitor dose-dependently (5–20 mg/kg) suppressed the vacuous chewing movements count in haloperidol-treated animals. In conclusion, the results of the present study infer that prostaglandins might play a significant role in the haloperidol-induced vacuous chewing movements, and prostaglandin synthesis inhibitors can serve as novel drug candidates for the treatment of tardive dyskinesia.     

Reversal of methamphetamine-induced behavioral sensitization by repeated administration of a dopamine D1 receptor agonist

Repeated intermittent administration of methamphetamine (MAP) produces an enduring hypersensitivity to the motor stimulant effect of MAP, termed behavioral sensitization. Dopamine plays a critical role in the development and expression of behavioral sensitization. Here, we investigated whether a dopamine D₁ receptor agonist could reverse behavioral sensitization to MAP. Administration of MAP (1.0 mg/kg, i.p.) to rats once every 3 days for a total of 5 times (days 1–13) induced the enhancement of locomotor activity after MAP challenge (0.5 mg/kg, i.p.) on day 20, verifying the development of behavioral sensitization. The MAP-sensitized rats then received a dopamine D₁ agonist, R-(+)-SKF38393 (3.0 mg/kg, i.p.), once a day for 7 consecutive days (days 21–27). Behavioral analysis on days 30 and 41 revealed that the enhanced locomotor activity was reversed by repeated R-(+)-SKF38393 administration. Moreover, repeated R-(+)-SKF38393 administration reversed the increased dopamine release in the striatum after MAP challenge on day 41. Thus, repeated administration of the dopamine D₁ receptor agonist induces the reversal of established behavioral sensitization to MAP and of increased dopamine release in the striatum, lasting for at least 2 weeks. Dopamine D₁ receptor agonists may be useful therapeutic agents for the treatment of psychostimulant addiction.     

Effects of prolyl-leucyl-glycinamide and cyclo(leucyl-glycine) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to rats

The effects of melanotropin release-inhibiting factor, a tripeptide (Pro-Leu-Gly-NH₂) derived from the hypothalamus, and its enzymatically stable analog, cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to male Sprague-Dawley rats was determined. Oral administration of haloperidol (1.5 mg/kg per day) for 21 days induced supersensitivity of dopamine receptors as shown by enhanced locomotor activity in response to apomorphine, and an increase in the number of binding sites for [³H]spiroperidol in the striatum. Subcutaneous administration of Pro-Leu-Gly-NH₂ or cyclo(Leu-Gly) in doses of 2 mg/kg per day, given prior to the injection of haloperidol, inhibited both the enhanced response to apormorphine as well as the increase in the number of binding sites for [³H]spiroperidol in the striatum. Chronic administration of either of the peptides alone did not modify either the apomorphine-induced response or the binding of [³H]spiroperidol in the striatum. These studies suggest that the hypothalamic peptide, Pro-Leu-Gly-NH₂ and its long-acting analog, cyclo (Leu-Gly) can prevent the development of both behavioral and biochemical supersensitivity of dopamine receptors in brain induced by neuroleptic drugs and that these peptides may be useful in preventing the development of neuroleptic-induced tardive dyskinesia.     

Haloperidol-induced vacuous chewing in rats: suppression by alpha-methyl-tyrosine.

Chronic treatment of rats with haloperidol (1 mg/kg twice daily for 4 weeks) induced repetitive vacuous chewing movements (VC), that persisted for over 72 h after haloperidol withdrawal. Haloperidol-induced VC were inhibited by the s.c. administration of the specific dopamine D1, receptor antagonist, SCH 23390 (0.025-0.100 mg/kg), in a dose-dependent manner, and were totally suppressed by an acute challenge with haloperidol (2 mg/kg i.p.) and by the dopamine synthesis inhibitor, alpha-methyl-tyrosine (AMT) (200 mg/kg i.p.). In AMT-treated rats, VC were reinstated by the administration of the selective D1 agonist, SKF 38393. The results support the hypothesis that chronic haloperidol-induced VC are mediated by dopamine acting selectively upon D1 receptors.