Dyskinesia In Rats Research Articles

Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats.

Treatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT1 A receptor, but these drugs have been reported to worsen PD features and are known to produce '5-HT syndrome', symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia. Sprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT1 A agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT1 A agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia. Each 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome. The results suggest that compounds that indirectly facilitate 5-HT1 A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT1 A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile.

L-DOPA-induced dyskinesia in a rat model of Parkinson's disease is associated with the fluctuational release of norepinephrine in the sensorimotor striatum.

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) is the most common complication of standard L-DOPA therapy for Parkinson's disease experienced by most parkinsonian patients. LID is associated with disruption of dopaminergic homeostasis in basal ganglia following L-DOPA administration. Norepinephrine (NE) is another important catecholaminergic neurotransmitter that is also believed to be involved in the pathogenesis of LID. This study compared NE release in the ipsilateral sensorimotor striatum of dyskinetic and nondyskinetic 6-hydroxydopamine-lesioned hemiparkinsonian rats treated chronically with L-DOPA. After L-DOPA injection, the time-course curves of NE levels in the sensorimotor striatum were significantly different between dyskinetic and nondyskinetic rats. Several metabolic kinetic parameters of NE levels were also differentially expressed between the two groups. In comparison with nondyskinetic rats, the ΔCmax of NE was significantly higher in dyskinetic rats, whereas Tmax and t1/2 of NE were significantly shorter. Intrastriatal perfusion of NE into the lesioned sensorimotor striatum revealed a moderate dyskinesia in dyskinetic rats, which was similar to the dyskinetic behavior after L-DOPA administration. The L-DOPA-related dyskinetic behavior was inhibited significantly by a further pretreatment of noradrenergic neurotoxin N-​(2-​chloroethyl)​-​N-​ethyl-​2-​bromobenzylamine or intrastriatal administration of the α2 -adrenoceptor antagonist idazoxan, accompanied by significant changes in metabolic kinetic parameters of NE in the sensorimotor striatum. The results provide evidence to support the correlation between abnormal NE neurotransmission and the induction of LID and suggest that the aberrant change of the quantitative and temporal releasing of NE in the sensorimotor striatum might play an important role in the pathogenesis of LID.

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the locus coeruleus, and associated pontine nuclei. Animals with combined DA and NA lesions were more prone to develop L-DOPA-induced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to brainstem NA neurons, contributes to the development of motor impairments and the appearance of L-DOPA-induced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons.

Anandamide attenuates haloperidol-induced vacuous chewing movements in rats.

Antipsychotics may cause tardive dyskinesia in humans and orofacial dyskinesia in rodents. Although the dopaminergic system has been implicated in these movement disorders, which involve the basal ganglia, their underlying pathomechanisms remain unclear. CB1 cannabinoid receptors are highly expressed in the basal ganglia, and a potential role for endocannabinoids in the control of basal ganglia-related movement disorders has been proposed. Therefore, this study investigated whether CB1 receptors are involved in haloperidol-induced orofacial dyskinesia in rats. Adult male rats were treated for four weeks with haloperidol decanoate (38mg/kg, intramuscularly - i.m.). The effect of anandamide (6nmol, intracerebroventricularly - i.c.v.) and/or the CB1 receptor antagonist SR141716A (30μg, i.c.v.) on haloperidol-induced vacuous chewing movements (VCMs) was assessed 28days after the start of the haloperidol treatment. Anandamide reversed haloperidol-induced VCMs; SR141716A (30μg, i.c.v.) did not alter haloperidol-induced VCM per se but prevented the effect of anandamide on VCM in rats. These results suggest that CB1 receptors may prevent haloperidol-induced VCMs in rats, implicating CB1 receptor-mediated cannabinoid signaling in orofacial dyskinesia.

Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in rat

Tardive dyskinesia is a serious motor disorder of the orofacial region, resulting from chronic neuroleptic treatment of schizophrenia. Candesartan (AT1 antagonist) and lisinopril (ACE inhibitor) has been reported to possess antioxidant and neuroprotective effects. The present study is designed to investigate the effect of candesartan and lisinopril on haloperidol-induced orofacial dyskinesia and oxidative damage in rats. Tardive dyskinesia was induced by administering haloperidol (1 mg/kg i.p.) and concomitantly treated with candesartan (3 and 5 mg/kg p.o.) and lisinopril (10 and 15 mg/kg p.o.) for 3 weeks in male Wistar rats. Various behavioral parameters were assessed on days 0, 7, 14 and 21 and biochemical parameters were estimated at day 22. Chronic administration of haloperidol significantly increased stereotypic behaviors in rats, which were significantly improved by administration of candesartan and lisinopril. Chronic administration of haloperidol significantly increased oxidative stress and neuro-inflammation in the striatum region of the rat's brain. Co-administration of candesartan and lisinopril significantly attenuated the oxidative damage and neuro-inflammation in the haloperidol-treated rat. The present study supports the therapeutic use of candesartan and lisinopril in the treatment of typical antipsychotic-induced orofacial dyskinesia and possible antioxidant and neuro-inflammatory mechanisms.

Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson's disease.

Compound Formula Rehmannia has been shown to be clinically effective in treating Parkinson's disease and levodopa-induced dyskinesia; however, the mechanisms remain unclear. In this study, we established a model of Parkinson's disease dyskinesia in rats, and treated these animals with Compound Formula Rehmannia. Compound Formula Rehmannia inhibited the increase in mRNA expression of N-methyl-D-aspartate receptor subunits 1 and 2 and excitatory amino acid neurotransmitter genes, and it inhibited the reduction in expression of γ-aminobutyric acid receptor B1, an inhibitory amino acid neurotransmitter gene, in the corpus striatum. In addition, Compound Formula Rehmannia alleviated dyskinesia symptoms in the Parkinson's disease rats. These experimental findings indicate that Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson's disease by modulating neurotransmitter signaling in the corpus striatum.

Ranitidine reduced levodopa-induced dyskinesia in a rat model of Parkinson’s disease

BackgroundChronic administration of levodopa in Parkinson’s disease leads to debilitating involuntary movements, termed levodopa-induced dyskinesia (LID). The pathogenesis of LID is poorly understood. Previous research has shown that histamine H2 receptors are highly expressed in the input (striatum) and output (globus pallidus, substantia nigra) regions of the basal ganglia, particularly in the GABAergic striatopallidal and striatonigral pathways. Therefore, a histamine H2 receptor antagonist could be used to reduce LID. In the present work, we investigated whether ranitidine has the potential to diminish LID in rats with dyskinesia and explored the underlying mechanisms involved.MethodsA rat model of PD was induced by 6-hydroxydopamine. Valid PD rats were then treated with levodopa (25 mg/kg, intraperitoneally) and benserazide (12.5 mg/kg, intraperitoneally) for 21 days to induce a rat model of LID. The acute and chronic effects of administration of ranitidine at different doses (5 mg/kg, 10 mg/kg, and 20 mg/kg) on abnormal involuntary movements, levodopa-induced rotations, and the forelimb adjusting steps test were investigated in LID rats. The chronic effect of ranitidine (10 mg/kg) on the expression of Arc and proenkephalin was also evaluated.ResultsLevodopa elicited increased dyskinesia in PD rats. Acute ranitidine treatment had no effect on LID, but chronic ranitidine administration (10 mg/kg, 20 mg/kg) reduced LID in rats with dyskinesia. Importantly, levodopa-induced rotations were not affected by chronic treatment with ranitidine. In addition, chronic ranitidine (10 mg/kg, 20 mg/kg) significantly improved stepping of the lesioned forepaw. Real-time polymerase chain reaction showed that Arc and proenkephalin levels were reduced by chronic ranitidine (10 mg/kg) in dyskinetic rats.ConclusionThese data indicate that ranitidine is a good adjunct for reducing LID in rats with dyskinesia. Inhibition of dopamine D1-mediated activation in the medium spiny neurons may account for the antidyskinetic effects of ranitidine in rats with dyskinesia.

Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson's disease

The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta that degenerates in Parkinson's disease. The present study aimed to investigate the role of dopaminergic denervation of STN in the origin of levodopa-induced dyskinesias. Rats were distributed in four groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the STN and in the medial forebrain bundle (MFB) as follows: a) MFB-sham plus STN-sham, b) MFB-sham plus STN-lesion, c) MFB-lesion plus STN-sham, and d) MFB-lesion plus STN-lesion. Four weeks after lesions, animals were treated with levodopa (6mg/kg with 15mg/kg benserazide i.p.) twice daily for 22 consecutive days. Abnormal involuntary movements were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin, STN cytochrome oxidase (CO) and nigral GAD67 mRNAs. STN 6-OHDA denervation did not induce dyskinesias in levodopa-treated MFB-sham animals but attenuated axial (p<0.05), limb (p<0.05) and orolingual (p<0.01) dyskinesias in rats with a concomitant lesion of the nigrostriatal pathway. The attenuation of dyskinesias was associated with a decrease in the ipsilateral STN CO mRNA levels (p<0.05). No significant differences between MFB-lesion plus STN-sham and MFB-lesion plus STN-lesion groups in the extent of STN dopaminergic denervation were observed. Moreover, intrasubthalamic microinfusion of dopamine in the MFB-lesion plus STN-lesion group triggered orolingual (p<0.01), but not axial or limb, dyskinesias. These results suggest that dopaminergic STN innervation influences the expression of levodopa-induced dyskinesias but also the existence of non dopaminergic-mediated mechanisms. STN noradrenergic depletion induced by 6-OHDA in the STN needs to be taken in account as a possible mechanism explaining the attenuation of dyskinesias in the combined lesion group.

Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia

Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Antagonists at glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity. The aim of this work was to evaluate alterations in alternative splicing of striatal AMPA receptor subunits in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID and PD. Male Sprague–Dawley rats received 12.5μg 6-OHDA injections into the right medial forebrain bundle. In experiment 1, to assess acute dyskinesia, rats received L-DOPA/benserazide (6/15mg/kg, i.p.) or vehicle for 21days. In experiment 2, to assess dyskinesia priming, rats received vehicle, L-DOPA+vehicle or L-DOPA+IEM 1460 (3mg/kg, i.p.) for 21days. Animals were humanely killed 1h following final treatment in experiment 1, and 48h following final treatment in experiment 2. Coronal sections of rostral striatum were processed for in situ hybridisation histochemistry, using oligonucleotide probes specific for the GluR1 and GluR2 subunits and their flip and flop isoforms. L-DOPA treatment increased GluR2-flip mRNA expression in the lesioned striatum of both groups; this was blocked by the Ca2+-permeable AMPA receptor antagonist IEM 1460. GluR1-flip expression was increased after 48h drug washout but not in acute LID. There were no changes in expression of flop isoforms. Alternative splicing of AMPAR subunits contributes to abnormal striatal plasticity in the induction and expression of LID. Increases in GluR2-flip expression depend on activation of Ca2+-permeable AMPA receptors, which are a potential target of anti-dyskinetic therapies.

Effects of Chinese herbal medicine Tianqi Pingchan Granule on G protein-coupled receptor kinase 6 involved in the prevention of levodopa-induced dyskinesia in rats with Parkinson disease

To investigate the effects of Tianqi Pingchan (TQPC) Granule, a compound traditional Chinese herbal medicine with antitremor activity, on levodopa-induced dyskinesia and the expression of G protein-coupled receptor kinase 6 (GRK6) in rats with Parkinson disease (PD). The hemi-Parkinsonian rat model was established by sterotaxically injecting 6-hydroxydopa (6-OHDA) to the right medial forebrain bundle. Rats with PD were randomly divided into 5 groups with 5 in each. PD group was intraperitoneally injected with vitamin C; levodopa group was intraperitoneally injected with levodopa and benserazide; low-, medium- and high-dose TQPC Granule groups were intraperitoneally injected with levodopa and benserazide and treated with different dosages of TQPC Granule by gavage for 29 d. Another 5 rats were served as control with sham-operation. The behaviors of rats were observed and classified with abnormal involuntary movement (AIM) score. The expression of GRK6 in the striate of rats was detected by immunohistochemical method and Western blotting. AIM score was increased and the expression of GRK6 protein in lesion side was decreased after the long-tern treatment with levodopa and benserazide in rats. The AIM scores of rats with PD were decreased after TGPC Granule treatment. Immunohistochemical results showed that the number of GRK6-positive cells in medium- and high-dose TQPC Granule groups was increased as compared to that in the levodopa group (P<0.05). The expression level of GRK6 protein was increased in medium-dose TQPC Granule group when compared with the levodopa group (P<0.01), which was observed by Western blotting. TGPC Granule can increase the expression of GRK6, inhibit the increase of AIM, and reduce the incidence of levodopa-induced dyskinesia in rats with PD.

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) have been proposed as a novel therapeutic approach for the treatment of Parkinson's disease. However, evaluation of this proposal has been limited by the availability of appropriate pharmacological tools to interrogate the target. In this study, we describe the properties of a novel mGluR4 PAM. 5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (ADX88178) enhances glutamate-mediated activation of human and rat mGluR4 with EC(50) values of 4 and 9 nM, respectively. The compound is highly selective for mGluR4 with minimal activities at other mGluRs. Oral administration of ADX88178 in rats is associated with high bioavailability and results in cerebrospinal fluid exposure of >50-fold the in vitro EC(50) value. ADX88178 reverses haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. It is noteworthy that this compound alone has no impact on forelimb akinesia resulting from a bilateral 6-hydroxydopamine lesion in rats. However, coadministration of a low dose of L-DOPA (6 mg/kg) enabled a robust, dose-dependent reversal of the forelimb akinesia deficit. ADX88178 also increased the effects of quinpirole in lesioned rats and enhanced the effects of L-DOPA in MitoPark mice. It is noteworthy that the enhancement of the actions of L-DOPA was not associated with an exacerbation of L-DOPA-induced dyskinesias in rats. ADX88178 is a novel, potent, and selective mGluR4 PAM that is a valuable tool for exploring the therapeutic potential of mGluR4 modulation. The use of this novel tool molecule supports the proposal that activation of mGluR4 may be therapeutically useful in Parkinson's disease.

Neuronal nitric oxide synthase inhibition attenuates the development of L-DOPA-induced dyskinesia in hemi-Parkinsonian rats

Long-term treatment with the dopamine precursor levodopa (l-DOPA) frequently induces dyskinesia in Parkinson's disease patients, which is a major complication of this therapy. Previous studies using animal models show that repeated administration of l-DOPA results in alterations of some signaling molecules, including ΔFosB, phospho-DARPP32 and phosoho-GluA1 (also referred to as GluR1 or GluR-A) AMPA receptor subunits. Moreover, an in vivo microdialysis study showed that l-DOPA increases nitric oxide (NO) production in the striatum. However, it is not known whether NO is involved in the development of dyskinesia. The present study examined the effects of NOS inhibitors on the development of l-DOPA-induced dyskinesia in the rats. Dyskinesia symptoms were triggered by daily administration of l-DOPA for 3–4weeks in unilateral 6-hydroxydopamine lesioned rats. Repeated treatments, 30min prior l-DOPA administration, of the nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester, and the nNOS inhibitor 7-nitroindazole, but not the inducible NOS inhibitor aminoguanidine, attenuated the development of l-DOPA-induced dyskinesia. In agreement with the behavioral analysis, 7-nitroindazole reduced the l-DOPA-induced increases in ΔFosB, phospho-DARPP32 and phospho-GluA1 AMPA receptor subunit levels in the striatum of 6-hydroxydopamine-lesioned rats. Furthermore, aminoguanidine did not affect ΔFosB or phospho-GluA1 AMPA receptor subunit levels. These findings suggest that nNOS-derived NO is involved in the development of l-DOPA-induced dyskinesia through a post-synaptic mechanism.

Amphetamine-Induced Dyskinesia in the Transplanted Hemi-Parkinsonian Mouse

The transplantation of dopamine-rich tissue into the putamen of patients with Parkinson's disease shows much potential for use as a therapeutic strategy. However, a number of grafted individuals subsequently developed a set of abnormal involuntary movements (AIMs), unrelated to the dyskinesia caused by L-DOPA treatment, which have been termed graft-induced dyskinesia. Given the small number of patients, pre-clinical modeling of graft-induced dyskinesia in animal models will be critical to determine the underlying mechanisms and amelioration potential of this technique. Here we show that abnormal involuntary movements of the limbs, trunk and face can be observed in transplanted hemi-parkinsonian mice following amphetamine administration, similar to those previously described to model graft-induced dyskinesias in rats. C57Bl6 and CD1 mice were first rendered hemi-parkinsonian with 6-hydroxydopamine, treated with L-DOPA for 21 days until dyskinetic, and then transplanted with a single cell suspension of embryonic ventral mesencephalon (VM E12.5) tissue from corresponding strains into the denervated striatum. At 16 weeks post-transplantation, a single injection of amphetamine-elicited dyskinesia in a subgroup of mice of both strains, behavioural pattern not observed pre-transplantation. The number of surviving dopaminergic cells in the graft did not differ between those that developed AIMs and those that did not. The movements were phenotypically comparable to those seen in the rat model and parallels can be drawn to the human form of the movements, although the mouse model maybe less reproducible than the rat equivalent. This mouse model will facilitate assessment of graft-induced dyskinesia with mouse-derived stem cell lines and exploration of mechanisms using transgenic mice in future studies.

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.

Effect of ammonium glycyrrhizinate on haloperidol- and reserpine- induced neurobehavioral alterations in experimental paradigms

The present work was aimed to assess the effect of ammonium glycyrrhizinate, AG (50, 100, and 150 mg/kg, i.p.) on haloperidol induced catalepsy in mice; reserpine induced orofacial dyskinesia in rats; and reserpine antagonism in mice. Additionally the effect of AG on lipid peroxidation (LP) in cataleptic mice brain and monoamine oxidase-B (MAO-B) levels in normal mice brain was assessed. Administration of AG 100 and 150 mg/kg showed significant reduction in the duration of cataleptic behavior at 60 to 180 min and dose dependent decrease in LP induced by haloperidol. AG showed significant decrease in frequency of vacuous chewing movements at 150 mg/kg and frequency of tongue protrusion at 100 and 150 mg/kg in reserpine induced orofacial dyskinesia test. AG showed significant increase in frequency of horizontal movement and rearing behavior at 150 mg/kg and increase in grooming behavior at 100 and 150 mg/kg in reserpine antagonism test. AG showed dose dependent inhibition of MAO-B in the normal mice brain. These results suggested that AG prevented the haloperidol- and reserpine- induced neurobehavioral alterations possibly by acting as free radical scavenger or inhibiting MAO-B thereby increasing dopaminergic transmition consequently decreasing dopamine metabolites and ultimately preventing the generation of free radicals.

Ethanolic extract of Rubia peregrina L. (Rubiaceae) inhibits haloperidol-induced catalepsy and reserpine-induced orofacial dyskinesia

In the traditional Sardinian system of medicine, Rubia peregrina L. (Rubiaceae) is reported as an aphrodisiac herb. Since the aphrodisiacs may also have antioxidant and dopaminergic activities, the aim of this study was to study the effect of ethanolic extract of aerial parts of R. peregrina for the scavenging of free DPPH radicals and the inhibition of haloperidol-induced catalepsy in mice and reserpine-induced orofacial dyskinesia in rats. The extract exhibited significant antioxidant activity in a free radical DPPH assay with IC50 = 55.6 µg mL−1, which was very close to IC50 of ascorbic acid. The extract of R. peregrina (100 and 200 mg kg−1 intraperitoneally, i.p.) significantly inhibited haloperidol (1 mg kg−1 i.p.) – induced catalepsy in mice (p < 0.01). In rats, the extract (200 mg kg−1 i.p.) significantly (p < 0.01) inhibited the orofacial dyskinesia induced by intraperitoneal administration of reserpine (1 mg kg−1 on days 1, 3 and 5). This study demonstrates that R. peregrina has antioxidant activity and improves the dopaminergic function. Results therefore justify the development of further experiments to investigate the psychopharmacological profile of R. peregrina.

Role of Nitric Oxide in Motor Control: Implications for Parkinson's Disease Pathophysiology and Treatment

According to classical thinking about Parkinson's disease, loss of dopaminergic input from the substantia nigra pars compacta leads to overactivity and underactivity of the indirect and direct output pathways, respectively, in the basal ganglia. Administration of the dopamine precursor L-DOPA (l-3, 4-dihydroxyphenylalanine) is proposed to induce changes in the opposite directions. L-DOPA is the most used drug to treat Parkinson`s disease symptoms. After repeated treatment with this compound, however, disabling secondary effects such as the abnormal involuntary movements usually appear. Nitric oxide is a free radical that can also act as an atypical neurotransmitter and influences dopamine-mediated neurotransmission. In this paper we will briefly review the role of nitric oxide on motor control and in Parkinson's disease, particularly a possible role of nitric oxide in L-DOPA induced dyskinesia in rodents. Recent results show that nitric oxide synthase inhibition reduces L-DOPA-induced dyskinesia in rats and mice. The effect is dose-dependent, does not suffer tolerance nor interferes with L-DOPA positive motor effects. These preclinical findings suggest that nitric oxide is a promising therapeutic target for the reduction of L-DOPA-induced dyskinesia.

An improved model to investigate the efficacy of antidyskinetic agents in hemiparkinsonian rats

A number of experimental models of L-DOPA-induced dyskinesia have been proposed, but these models result in a low to medium rate of dyskinetic animals with mild to severe symptoms. The objective of this study was to combine a model of 6-OHDA-induced parkinsonism and of L-DOPA-induced dyskinesia in rats to establish a reliable preclinical model. Two stereotaxic injections of 6-OHDA were administered in the left striatum. This model led to 90-100% of rats with a marked contralateral circling behaviour, significant limb use asymmetry (20%), a decrease in ipsilateral striatal dopamine content (70%) and degeneration of dopamine neurons in the substantia nigra (70%). Chronic treatment with L-DOPA was administered for 35 days and consisted of three phases with incremental daily doses. The third phase resulted in 83-90% of rats developing severe abnormal involuntary movements (AIMs) which included limb and locomotive dyskinesia, axial dystonia and orolingual dyskinesia. Reproducibility of the model, criteria of strict blinding, placebo-controlled design, randomization of study subjects and pretrial determination of sample size were used to measure efficacy of amantadine and istradefylline and to validate the protocol design. Acute or subchronic post-treatment with amantadine reduced the severity of dyskinesia while istradefylline punctually attenuated AIMs. Our experimental conditions using gradual development of dyskinesia induced by increasing doses of L-DOPA resulted in a reliable model of L-DOPA-induced dyskinesia with a high rate of dyskinetic rats.

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.

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Drug-induced dyskinesias in dopamine-denervated animals are known to depend on both pre- and postsynaptic changes of the nigrostriatal circuitry. In lesion models used thus far, changes occur in both of these compartments and, therefore, it has not been possible to dissect the individual contribution of each compartment in the pathophysiology of dyskinesias. Here we silenced the nigrostriatal dopamine neurotransmission without affecting the anatomical integrity of the presynaptic terminals using a short-hairpin RNA-mediated knockdown of tyrosine hydroxylase enzyme (shTH). This treatment resulted in significant reduction (by about 70%) in extracellular dopamine concentration in the striatum as measured by on-line microdialysis. Under these conditions, the animals remained nondyskinetic after chronic L-DOPA treatment, whereas partial intrastriatal 6-hydoxydopamine lesioned rats with comparable reduction in extracellular dopamine levels developed dyskinesias. On the other hand, apomorphine caused moderate to severe dyskinesias in both groups. Importantly, single-dose L-DOPA challenge in apomorphine-primed shTH animals failed to activate the already established abnormal postsynaptic responses. Taken together, these data provide direct evidence that the status of the presynaptic, DA releasing compartment is a critical determinant of both the induction and maintenance of L-DOPA-induced dyskinesias.