Tremor In Rats Research Articles

Epicranial Direct Current Stimulation Suppresses Harmaline Tremor in Rats

IntroductionEssential tremor (ET) is the most common neurologic movement disorder worldwide. It is characterized by a postural tremor, mostly in the upper extremities, causing difficulties in daily activities that may lead to social exclusion. Some patients with ET do not respond well to or do not tolerate medication. Thus, deep brain stimulation can be offered. In a recent study, we proposed a novel neuromodulation technique called epicranial current stimulation (ECS) that works in a minimally invasive way by placing the electrodes subcutaneously under the skin and directly over the skull. In this study, we investigated the feasibility of using epicranial direct current stimulation (EDCS) to suppress tremor in a rat harmaline ET model. Materials and MethodsIn experiment 1, seven Sprague Dawley rats were implanted with ECS electrodes placed over the motor cortex (MC) and the cerebellum to investigate whether stimulating between them could suppress tremor. In experiments 2 and 3, eight rats were implanted with ECS electrodes placed over the MC, cerebellum, and the rostral skull to separate the effects on tremor caused by stimulating each target. During each experiment, the rats were injected with harmaline, which induced tremor that was quantified using an accelerometer. EDCS was then applied through the different electrode configurations to evaluate their tremor suppression effectiveness. ResultsResults from experiment 1 showed that MCcathode-Cerebellaranode suppressed tremor compared with stimulation-OFF but MCanode-Cerebellarcathode did not. Furthermore, experiments 2 and 3 showed that it was the cerebellar anodal electrode that was driving tremor suppression. ConclusionCerebellar EDCS suppressed harmaline tremor in rats in a polarity-dependent manner. EDCS could be a promising neuromodulation method for patients with ET.

Phytohormone abscisic acid elicits positive effects on harmaline-induced cognitive and motor disturbances in a rat model of essential tremor.

ObjectiveEssential tremor (ET) as a neurological disorder is accompanied by cognitive and motor disturbances. Despite the high incidence of ET, the drug treatment of ET remains unsatisfactory. Recently, abscisic acid (ABA) has been reported to have positive neurophysiological effects in mammals. Here, the effects of ABA on harmaline‐induced motor and cognitive impairments were investigated in rats.MethodsMale Wistar rats weighing 120–140 g were divided into control, harmaline (30 mg/kg, ip), ABA vehicle (DMSO+normal saline), and ABA (10 μg/rat, icv, 30 min before harmaline injection) groups. Exploratory, balance and motor performance, anxiety, and cognitive function were assessed using footprint, open field, wire grip, rotarod, and shuttle box tests.ResultsThe results indicated that ABA (10 μg/rat) can improve harmaline‐induced tremor in rats. The administration of ABA significantly increased time spent on wire grip and rotarod. In addition, ABA had a promising effect against the cognitive impairments induced by harmaline.ConclusionTaken together, ABA has positive effects on locomotor and cognitive impairments induced by tremor. However, further studies are required to determine the exact mechanisms of ABA on the ET.

Polarity dependent epicranial direct current stimulation over the cerebellum suppresses Harmaline tremor in rats

Abstract Background: Essential tremor (ET) is a neurological movement disorder that manifest a tremor in different body parts, but mainly the hands, leading to movement disability and social withdrawal. It is the most prevalent movement disorder with more than half of the patients not achieving satisfactory tremor reduction using medication. Thus, deep brain stimulation (DBS) becomes a standard treatment. However, DBS is highly invasive with stimulation electrodes being implanted in deep brain regions. To overcome that, the motor and the cerebellar cortex have been suggested as an alternative, more superficial, targets for stimulation. While results from an epidural cortical stimulation study were promising, this technique remains highly invasive requiring a craniotomy to implant the electrodes. Recently, we proposed a novel minimally invasive neuromodulation technique, epicranial current stimulation (ECS), that can deliver strong cortical current through subcutaneous electrodes. Here, we used Harmaline ET model in rats to test the ability of direct current epicranial current stimulation (DC-ECT) in reducing tremor. Methods: Rats were implanted with discrete epicranial electrodes placed over the motor cortices, the cerebellum and the frontal cortex. After surgery recovery, the rats were injected with Harmaline (15 mg/kg) to induce tremor which was measured using an accelerometer. Then DC-ECT was applied and different electrodes configurations were used to test the effects of stimulation on tremor suppression. Results: Our results show that DC-ECT suppresses Harmaline tremor in rats. Cerebellar stimulation showed a significant decrease in tremor compared to no stimulation. This effect was polarity dependent with anodal stimulation showing tremor reduction but not cathodal one. Conclusion: DC-ECT is a very promising neuromodulation technique that can suppress harmaline induced tremor in rats. Given its minimally invasive nature, it could be an alternative to DBS for ET patients. Keywords: epicranial stimulation, Essential tremor, Harmaline, Direct current stimulation

Agmatine has beneficial effect on harmaline-induced essential tremor in rat

Essential tremor (ET) is one of the most prevalent movement disorders and the most common cause of abnormal tremors. However, it cannot be treated efficiently with the currently available pharmacotherapy options. The pathophysiology of harmaline-induced tremor, most commonly used model of ET, involves various neurotransmitter systems including glutamate as well as ion channels. Agmatine, an endogenous neuromodulator, interacts with various glutamate receptor subtypes and ion channels, which have been associated with its’ beneficial effects on several neurological disorders. The current study aims to assess the effect of agmatine on the harmaline model of ET. Two separate groups of male rats were injected either with saline or agmatine (40 mg/kg) 30 min prior to single intraperitoneal injection of harmaline (20 mg/kg). The percent duration, intensity and frequency of tremor and locomotor activity were evaluated by a custom-built tremor and locomotion analysis system. Pretreatment with agmatine reduced the percent tremor duration and intensity of tremor induced by harmaline, without affecting the tremor frequency. However, it did not affect the decreased spontaneous locomotor activity due to harmaline. This pattern of ameliorating effects of agmatine on harmaline-induced tremor provide the first evidence for being considered as a treatment option for ET.

Pramipexole Reduces zif-268 mRNA Expression in Brain Structures involved in the Generation of Harmaline-Induced Tremor

Essential tremor is one of the most common neurological disorders, however, it is not sufficiently controlled with currently available pharmacotherapy. Our recent study has shown that pramipexole, a drug efficient in inhibiting parkinsonian tremor, reduced the harmaline-induced tremor in rats, generally accepted to be a model of essential tremor. The aim of the present study was to investigate brain targets for the tremorolytic effect of pramipexole by determination of the early activity-dependent gene zif-268 mRNA expression. Tremor in rats was induced by harmaline administered at a dose of 15 mg/kg ip. Pramipexole was administered at a low dose of 0.1 mg/kg sc. Tremor was measured by Force Plate Actimeters where four force transducers located below the corners of the plate tracked the animal’s position on a Cartesian plane. The zif-268 mRNA expression was analyzed by in situ hybridization in brain slices. Harmaline induced tremor and increased zif-268 mRNA levels in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei and motor cortex. Pramipexole reversed both the harmaline-induced tremor and the increase in zif-268 mRNA expression in the inferior olive, cerebellar cortex and motor cortex. Moreover, the tremor intensity correlated positively with zif-268 mRNA expression in the above structures. The present results seem to suggest that the tremorolytic effect of pramipexole is related to the modulation of the harmaline-increased neuronal activity in the tremor network which includes the inferior olive, cerebellar cortex and motor cortex. Potential mechanisms underlying the above pramipexole action are discussed.

Anti-Tremor Action of Subtype Selective Positive Allosteric Modulators of GABAA Receptors in a Rat Model of Essential Tremors.

Essential tremor (ET) is among the most prevalent neurological disorders and the most common cause of abnormal tremors. It is characterized by postural and action tremors ranging from 4 to 12Hz. The treatments of choice for ET are propranolol and primidone, but their use is associated with adverse effects like hypotension, depression, and cognitive impairments. Benzodiazepines, which nonselectively enhances the effect of GABA at the GABAA α1/2/3/5 receptors, have been shown to be effective in treating ET. Their use, however, is limited due to sedation, ataxia, tolerance development and memory impairment. Sedation and ataxia are attributed to the activity at the α1 subunit while cognitive impairment is ascribed to the action on the α5 subunit of the GABAA receptors. It can be hypothesized that subtype selective GABAA receptor modulators only acting via the α2, and α3 subunits may have an improved side effect profile while retaining the beneficial effects. Here, we have evaluated the effect of subtype selective GABAA α2/3/5 receptor modulators on harmaline-induced tremors in rats. The tremors were automatically quantified in tremor boxes. We show that the GABAA α2/3 subtype selective modulator NS16085 significantly and dose-dependently inhibits harmaline-induced tremors in rats, indicating that potentiation of α2- and α3-containing GABAA receptors is sufficient to ameliorate harmaline-induced tremors. These results provide the first support for a therapeutic role of a subtype selective GABAA α2/3 modulator in the treatment of ET.

Neuroanatomical correlates of the inhibition of tremulous jaw movements in rats by a combination of memantine and Δ9 -tetrahydrocannabinol.

Memantine and marijuana smoking have been found to inhibit tremor in parkinsonian patients, although the observed effects were relatively weak. The tremorolytic effects of combinations of memantine and cannabinoids have not been studied. Here, we have evaluated the anti-tremor activity of memantine, Δ9 -tetrahydrocannabinol (THC) given alone and of their combination. The involvement of some neuroanatomical structures in the effects of the combination was evaluated. Haloperidol-induced tremulous jaw movements (TJMs) in rats were used as a model of parkinsonian-like tremor. To evaluate the role of central receptor systems in the drug effects, receptor ligands were administered locally into certain brain areas. Memantine and THC alone were without effect, although co-administration of these drugs decreased the number of haloperidol-induced jaw movements. The anti-tremor activity of the combination was antagonized (a) by injections of l-glutamate into the dorsal striatum, entopeduncular nucleus, substantia nigra pars reticulata, globus pallidus, and supratrigeminal and trigeminal motor nuclei but not into the subthalamic and cuneiform nuclei; (b) by injections of CGS 21680 into the ventrolateral striatum; and (c) by injections of bicuculline into the rostral part of the parvicellular reticular nucleus. Memantine and THC supra-additively inhibit haloperidol-induced TJMs, suggesting that co-administration of these drugs might be a new approach to the treatment of tremor. Our results identified brain areas influencing parkinsonian-like tremor in rats and can help advance the development of novel treatments for repetitive involuntary movements.

STUDY OF RAPITALAM INFLUENCE ON OXOTREMORINE-INDUCED TREMOR

Parkinson’s disease is the second most common (after Alzheimer’s) neurodegenerative disease. All over the world, there is a search for new drugs aimed at the treatment of Parkinson’s disease. Till up to the present, there is no “ideal” medicine that can completely cure this disease and has minimal adverse side effects. Belgorod research institute of pharmacology of living systems is studying Rapitalam, a new drug for the treatment of tremulous Parkinson’s disease. This is an agonist of the mGluR4 group of metabotropic receptors.The aim of the article is to study Rapitalam influence on the oxotremorine-induced tremor in rats.Methods. The study comprised 60 rats (6 groups of 10 males), which were administered intragastrically with the studied substances for 10 days. All the animal groups except Control group 1, were administered with Rapitalam and the reference drug Levodopa. 30 minutes after Rapitalam and Levodopa, they were administered abdominally with the solution of Oxotremorine at the dose of 1.5 mg/kg. The animals of Control group 1, instead of Oxotremorine, were similarly administered with a solvent of 0.9% sodium chloride in the equivalent volume.Results. In comparison with the reference group, Rapitalam at the dose of 3 mg/kg significantly reduced the severity of tremor 50 min. after its administration. The same effect took place 30 min after the administration of Oxotremorine at the dose of 10 mg/kg. At the dose of 3 and 10 mg/kg, Rapitalam also decreased the number of rats in the group (in %) with the signs of tremor 60 min. and 50 min. after the administration of Oxotremorine, respectively.Conclusion. The study revealed that Rapitalam has a pronounced anti-tremor effect. Its administration at the studied doses reduced the symptoms of Oxotremorine-induced tremor in rats.

IN VIVO STUDY OF THE ACTION MECHANISM OF THE RAPITALAM PHARMACEUTICAL SUBSTANCE

The aimis to study the action mechanisms of the Rapitalam pharmaceutical substance using Parkinsonian syndrome models.Materials and methods.Various effects of a new pharmacological substance, N-chlorophenylmethyl-dihydro-methoxy-methylphenyl-oxopyridazine carboxamide (Rapitalam), were studied in male laboratory mice and rats. During the experiment, the various models of the Parkinsonian syndrome were reproduced: the simulation of the Parkinsonian syndrome by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) neurotoxin, the simulation of haloperidol-induced catalepsy, the simulation of apomorphine-induced stereotypy and the simulation of oxotremorine-induced tremor followed by tests. The following tests were carried out in order to determine the Rapitalam efficacy with regard to symptoms manifested after the MPTP administration in animals: the open field test, the rotarod performance test, as well as the evaluation of the grip strength and the degree of rigidity using the stride length. When simulating the haloperidol-induced catalepsy, a horizontal bar test was performed. After the administration of apomorphine, the severity of stereotypy was assessed in scores. A simulation of oxotremorine-induced tremor in rats was used to study the cholinergic link. After the administration of oxotremorine, the severity of tremor was assessed against the background of administration of the test compounds.Results.During the analysis of the data obtained in the open field and rotarod tests as well as the stride length and the grip force when simulating the Parkinsonian syndrome by introducing MPTP, no intergroup statistical differences were found. Thus, the tested Rapitalam substance in doses of 2 mg/kg, 6 mg/kg and 20 mg/kg and the Levodopa reference drug at a dose of 60 mg/kg had no effect on the indices of motor activity and motor coordination in mice when administered orally for 10 days. Rapitalam in doses of 1 mg/kg, 3 mg/kg and 10 mg/kg as well as the Levodopa reference drug at a dose of 50 mg/kg, did not affect the severity of haloperidol-induced catalepsy and apomorphine-induced stereotypy in rats. Under the administration of oxotremorine to laboratory animals, a statistically significant decrease in the severity of tremor was observed during the Rapitalam administration in doses of 3 mg/kg and 10 mg/kg.Conclusion.Rapitalam is established to have no effect on motor impairment due to dopaminergic mechanisms. The tested substance is characterized by a pronounced cholinoblocking effect at doses of 3 mg/kg and 10 mg/kg.Conflict of interest: the author declares no conflict of interest.

Targeting KCa1.1 Channels with a Scorpion Venom Peptide for the Therapy of Rat Models of Rheumatoid Arthritis.

Fibroblast-like synoviocytes (FLSs) are a key cell type involved in rheumatoid arthritis (RA) progression. We previously identified the KCa1.1 potassium channel (Maxi-K, BK, Slo 1, KCNMA1) as a regulator of FLSs and found that KCa1.1 inhibition reduces disease severity in RA animal models. However, systemic KCa1.1 block causes multiple side effects. In this study, we aimed to determine whether the KCa1.1 β1-3-specific venom peptide blocker iberiotoxin (IbTX) reduces disease severity in animal models of RA without inducing major side effects. We used immunohistochemistry to identify IbTX-sensitive KCa1.1 subunits in joints of rats with a model of RA. Patch-clamp and functional assays were used to determine whether IbTX can regulate FLSs through targeting KCa1.1. We then tested the efficacy of IbTX in ameliorating disease in two rat models of RA. Finally, we determined whether IbTX causes side effects including incontinence or tremors in rats, compared with those treated with the small-molecule KCa1.1 blocker paxilline. IbTX-sensitive subunits of KCa1.1 were expressed by FLSs in joints of rats with experimental arthritis. IbTX inhibited KCa1.1 channels expressed by FLSs from patients with RA and by FLSs from rat models of RA and reduced FLS invasiveness. IbTX significantly reduced disease severity in two rat models of RA. Unlike paxilline, IbTX did not induce tremors or incontinence in rats. Overall, IbTX inhibited KCa1.1 channels on FLSs and treated rat models of RA without inducing side effects associated with nonspecific KCa1.1 blockade and could become the basis for the development of a new treatment of RA.

Modulation of sphingosine-1-phosphate receptor ameliorates harmaline-induced essential tremor in rat.

Essential tremor (ET) is one of the most common movement disorders with unknown etiology. Despite lack of effective clinical treatments, some potential therapeutic factors and modulation of some neurotransmitters have been utilized to ameliorate motor symptoms in the animal models of tremor. In the current study, male Wistar rats (n=10 in each group) weighing 40-60g were divided into vehicle control groups (saline or DMSO), saline/DMSO+harmaline (30mg/kg, i.p.)+fingolimod (FTY720) (1mg/kg, i.p, 1h before harmaline injection) groups. Open field, rotarod, wire grip and foot print tests were used to evaluate motor function. The results demonstrated that administration of FTY720 can improve harmaline-induced tremor in rats. Moreover, FTY720 ameliorated gait disturbance. The results showed that FTY720 can recover step width, left and right step length; however, FTY720 failed to recover mobility duration. FTY720 also improved falling time and time spent in wire grip and rotarod, respectively. The current study provides the first evidence for the effectiveness of FTY720 on motor function in the harmaline model of ET. Furthermore, neuroprotective effects of FTY720 demonstrated in this study offer sphingosine-1-phosphate receptor (S1PR) modulators as a potential neuroprotective candidate against substance-induced tremor and a possible strategy for the treatment of patients with tremor.

Tremorolytic effect of 5'-chloro-5'-deoxy-(±)-ENBA, a potent and selective adenosine A1 receptor agonist, evaluated in the harmaline-induced model in rats.

The aim of this study was to examine the role of adenosine A1 receptors in the harmaline-induced tremor in rats using 5'-chloro-5'-deoxy-(±)-ENBA (5'Cl5'd-(±)-ENBA), a brain-penetrant, potent, and selective adenosine A1 receptor agonist. Harmaline was injected at a dose of 15mg/kg ip and tremor was measured automatically in force-plate actimeters by an increased averaged power in the frequency band of 9-15Hz (AP2) and by tremor index (a difference in power between AP2 and averaged power in the frequency band of 0-8Hz). The zif-268 mRNA expression was additionally analyzed by in situ hybridization in several brain structures. 5'Cl5'd-(±)-ENBA (0.05-0.5mg/kg ip) dose dependently reduced the harmaline-induced tremor and this effect was reversed by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective antagonist of adenosine A1 receptors (1mg/kg ip). Harmaline increased the zif-268 mRNA expression in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei, and motor cortex. 5'Cl5'd-(±)-ENBA reversed these increases in all the above structures. DPCPX reduced the effect of 5'Cl5'd-(±)-ENBA on zif-268 mRNA in the motor cortex. This study suggests that adenosine A1 receptors may be a potential target for the treatment of essential tremor.

Low-dose acute vanillin is beneficial against harmaline-induced tremors in rats

Objective: To study the effect of pretreatment with low doses of vanillin, a flavoring agent used as a food additive, on harmaline-induced tremor in rats.Methods: Sprague Dawley rats (110 ± 5 g) were divided into groups of six animals each. Vanillin (6.25 mg, 12.5 mg, and 25 mg/kg) was administered by gavage to different groups of rats, 30 minutes before the induction of tremor. Harmaline (10 mg/kg, i.p.) was used for the induction of tremor. The latency of onset, duration, tremor intensity, tremor index, and spontaneous locomotor activity were recorded. A separate batch of animals was used for the determination of serotonin (5HT) and 5 hydroxyindole acetic acid (5HIAA) levels in the brain.Results: Harmaline treatment resulted in characteristic tremor that lasted for more than 2 hours and decreased the locomotor activity of rats. Pre-treatment with vanillin significantly reduced the duration, intensity, and tremor index of harmaline-treated animals. Vanillin treatment also significantly attenuated harmaline-induced decrease in the locomotor activity. An increase in 5HT levels and the changes in 5HIAA/5HT ratio observed in harmaline treated rats were significantly corrected in vanillin pretreated animals.Discussion: Vanillin in low doses reduces harmaline-induced tremor in rats, probably through its modulating effect on serotonin levels in the brain. These findings suggest a beneficial effect of vanillin in essential tremor.

Cannabinoid type 1 receptor antagonism ameliorates harmaline-induced essential tremor in rat.

Essential tremor (ET) is a neurological disorder with unknown aetiology. Its symptoms include cerebellar motor disturbances, cognitive and personality changes, hearing and olfactory deficits. Hyperactivity of excitotoxic cerebellar climbing fibres may underlie essential tremor and has been induced in rodents by systemic harmaline administration. Cannabinoid (CB) receptor agonists can cause motor disturbances; although, there are also anecdotal reports of therapeutic benefits of cannabis in motor disorders. We set out to establish the effects of CB receptor agonism and antagonism on an established rodent model of ET using a battery of accepted behaviour assays in order to determine the risk and therapeutic potential of modulating the endocannabinoid system in ET. Behavioural effects of systemic treatment with a CB receptor agonist (0.1, 0.5 and 1mgkg-1 WIN55, 212-2) or two CB1 receptor antagonists (1mgkg-1 AM251 and 10mgkg-1 rimonabant) on tremor induced in rats by harmaline (30mgkg-1 ; i.p.), were assessed using tremor scoring, open field, rotarod, grip and gait tests. Overall, harmaline induced robust tremor that was typically worsened across the measured behavioural domains by CB receptor agonism but ameliorated by CB1 receptor antagonism. These results provide the first evidence of the effects of modulating the endocannabinoid system on motor function in the harmaline model of ET. Our data suggest that CB1 receptor manipulation warrants clinical investigation as a therapeutic approach to protection against behavioural disturbances associated with ET.

Vanillin a Food Additive Ameliorates Harmaline Induced Tremor in Rats

Vanillin a Food Additive Ameliorates Harmaline Induced Tremor in Rats

Pramipexole at a Low Dose Induces Beneficial Effect in the Harmaline-induced Model of Essential Tremor in Rats.

The aim of the study was to examine the effects of preferential agonists of dopamine D3 receptors: pramipexole and 7-OH-DPAT on the harmaline-induced tremor in rats (a model of essential tremor, ET). To study receptor mechanisms of these drugs, rats were pretreated with dopamine D3 receptor antagonists--SB-277011-A and SR-21502, an antagonist of presynaptic D2/D3 receptors--amisulpride, or a nonselective antagonist of D2-like receptors, haloperidol, at a postsynaptic dose. For tremor measurement, fully automated force plate actimeters were used and data were analyzed using fast Fourier transform. Harmaline (15 mg/kg ip)-triggered tremor was manifested by an increase in the power within 9-15 Hz band (AP2). Pramipexole administered at a low (0.1 mg/kg sc), but not higher doses (0.3 and 1 mg/kg sc), and 7-OH-DPAT (0.1, 0.3, and 1 mg/kg sc) reversed the harmaline-increased AP2. None of the examined dopamine antagonists: SB-277011-A (10 mg/kg ip), SR-21502 (15 mg/kg ip), haloperidol (0.5 mg/kg ip), or amisulpride (1 mg/kg ip) influenced the above effect of dopamine agonists. The present study indicates that pramipexole reduces the harmaline-induced tremor, which may suggest its beneficial effects in ET patients. However, mechanisms underlying its action are still unclear and need further examination.

The therapeutic potential of Berberine chloride hydrate against harmaline-induced motor impairments in a rat model of tremor

Essential tremor (ET) is a progressive neurological disorder with motor and non-motor symptoms. It has conclusively been shown that modulation of glutamate receptors could ameliorate ET. Recent studies have suggested that Berberine (BBR) has an inhibitory effect on glutamate receptors. Therefore, BBR may have therapeutic effects on ET. In this study, male Wistar rats (n=10 in each group) weighing 40–60g were divided into control, harmaline (30mg/kg, i.p.) and berberine (10, 20 or 50mg/kg, i.p, 15min before harmaline injection) groups. Open field, rotarod, wire grip and foot print tests were used to evaluate motor performance. The results indicated that the administration of BBR (10 and 20mg/kg) attenuated harmaline-induced tremor in rats, but the beneficial effects of BBR could not be identified at dose 50mg/kg. In addition, BBR ameliorated gait disturbance in doses of 10 and 20mg/kg. The high dose of BBR not only failed to recover step width but also showed an adverse effect on left and right step length. The results indicate that BBR only in dose of 20mg/kg recovers mobility duration. The current study found a dose-dependent manner for the therapeutic effects of BBR in ET. Our study provides the initial evidence for the effects of BBR on motor function. Since BBR exerts its effects mainly through regulation of neurotransmitter release or blocke of NMDA receptors, thus, it is predicted that BBR ameliorate harmaline effect through blockade of NMDA receptors or glutamate release. This is an important issue for future research to evaluate the possible mechanisms involved.

Apomorphine enhances harmaline-induced tremor in rats

BackgroundHarmaline-induced tremor is a well-known model of essential tremor in humans. The aim of the present study was to examine the influence of apomorphine, a non-selective dopamine receptor agonist, on the tremor induced by harmaline in rats. Propranolol (a first-line drug in essential tremor) was used as a reference compound. MethodsTremor, locomotor activity and focused stereotypy were measured objectively using force plate actimeters. Tremor was analyzed using a Fourier transform to generate power spectra for rhythmic behavior. ResultsThe tremor induced by harmaline administered at a dose of 15mg/kg ip was associated with an increase in power in the 9–15Hz band (AP2) and in the tremor index, calculated as a difference between AP2 and power in the 0–8Hz band (AP1). Propranolol injected at a dose of 20mg/kg ip reversed both of these effects of harmaline. Apomorphine administered at the doses of 0.5 and 1mg/kg sc further enhanced AP2 and at the lower dose also the tremor index elevated by harmaline. This increase in AP2 was stronger than enhancement of locomotor activity induced by apomorphine in the harmaline-treated animals. ConclusionsThe present study suggests that the dopamine agonist apomorphine enhances the tremor induced by harmaline, and this effect is at least partly independent of hyperactivity.

Lu AF21934, a positive allosteric modulator of mGlu4 receptors, reduces the harmaline-induced hyperactivity but not tremor in rats

Harmaline induces tremor in animals resembling essential tremor which has been suggested to result from activation of the glutamatergic olivo-cerebellar projection. The aim of the present study was to examine the effects of systemic administration of Lu AF21934, a brain-penetrating positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4), on the harmaline-induced tremor and other forms of motor activity in rats using fully automated Force Plate Actimeters. The influence of harmaline on the mGlu4 mRNA expression in the cerebellum and inferior olive was analysed by in situ hybridization. Harmaline at a dose of 15 mg/kg (ip) triggered tremor which was manifested by an increase in the power within 9–15 Hz band and in the tremor index (a difference in power between bands 9–15 Hz and 0–8 Hz). Harmaline induced a biphasic effect on mobility, initially inhibiting the exploratory locomotor activity of rats (0–30 min after administration), followed by an increase in their basic activity. Lu AF21934 (0.5–5 mg/kg sc) did not influence tremor but at doses of 0.5 and 2.5 mg/kg reversed harmaline-induced hyperactivity. MGlu4 mRNA expression was high in the cerebellar cortex and low in the inferior olive. Repeated harmaline (15 mg/kg ip once a day for 5 days] decreased mGlu4 mRNA in the cerebellum and inferior olive.The present study indicates that the mGlu4 stimulation counteracts hyperactivity induced by harmaline which suggests the involvement of cerebellar glutamatergic transmission in this process. In contrast, neuronal mechanisms involved in tremor seem to be insensitive to the stimulation of mGlu4.

Effects of unilateral stereotactic posterior striatotomy on harmaline-induced tremor in rats

Although long known and the most prevalent movement disorder, pathophysiology of essential tremor (ET) remains controversial. The most accepted hypothesis is that it is caused by a dysfunction of the olivocerebellar system. Vilela Filho et al. [2001; Stereotact Funct Neurosurg 77:149-150], however, reported a patient with unilateral hand ET that was completely relieved after a stroke restricted to the contralateral posterior putamen and suggested that ET could be the clinical manifestation of posterior putamen hyperactivity. The present study was designed to evaluate this hypothesis in the most often used model of ET, harmaline-induced tremor in rats. Fifty-four male Wistar rats were randomly distributed into three groups: experimental (EG), surgical control (SCG), and pharmacological control (PCG) groups. EG animals underwent stereotactic unilateral posterior striatotomy. SCG rats underwent sham lesion at the same target. PCG served exclusively as controls for harmaline effects. All animals received, postoperatively, intraperitoneal harmaline, and the induced tremor was video-recorded for later evaluation by a blind observer. Thirteen animals were excluded from the study. Limb tremor was reduced ipsilaterally to the operation in 20 of 21 rats of EG and in two of nine of SCG, being asymmetric in one of 10 of PCG rats. Comparisons between EG × SCG and EG × PCG were statistically significant, but not between SCG × PCG. Limb tremor reduction was greater in anterior than in posterior paws. Lateral lesions yielded better results than medial lesions. These results suggest that the posterior striatum is involved with harmaline-induced tremor in rats and support the hypothesis presented.