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Adrian Handforth - One of the best experts on this subject based on the ideXlab platform.
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Octanoic Acid Suppresses Harmaline-Induced Tremor in Mouse Model of Essential Tremor
Neurotherapeutics, 2012Co-Authors: Fatta B. Nahab, Adrian Handforth, Arnulfo Quesada, Tyler Brown, Christopher Shin, Chuanhui Dong, Dietrich Haubenberger, Mark HallettAbstract:Recent work exploring the use of high-molecular weight alcohols to treat essential Tremor (ET) has identified octanoic acid as a potential novel Tremor-suppressing agent. We used an established harmaline-based mouse model of ET to compare Tremor suppression by 1-octanol and octanoic acid. The dose-related effect on digitized motion power within the Tremor bandwidth as a fraction of overall motion power was analyzed. Both 1-octanol and octanoic acid provided significant reductions in harmaline Tremor. An 8-carbon alkyl alcohol and carboxylic acid each suppress Tremor in a pre-clinical mouse model of ET. Further studies are warranted to determine the safety and efficacy of such agents in humans with ET.
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Comparison of mibefradil and derivative NNC 55-0396 effects on behavior, cytochrome P450 activity, and Tremor in mouse models of essential Tremor
European journal of pharmacology, 2011Co-Authors: Arnulfo Quesada, Gregg E. Homanics, Peter H. Bui, Oliver Hankinson, Adrian HandforthAbstract:Abstract NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2, 3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride], is a mibefradil derivative that retains potent in vitro T-type calcium channel antagonist efficacy. We compared the two compounds for behavioral toxicity, effects on cytochrome P450 activity, and efficacy against Tremor in the γ-aminobutyric acid type A (GABAA) receptor subunit α1-null mouse, and the harmaline Tremor model of essential Tremor in wild-type mice. NNC 55-0396 was better tolerated than mibefradil in the horizontal wire test of sedation/motor function, with 3/6 failing at 300 and 30 mg/kg respectively. To assess for a potential interaction with harmaline, mice were given the drugs, followed by harmaline or vehicle, and tested 30 min later in the inverted wire grid test. Mibefradil exacerbated, whereas NNC 55-0396 ameliorated Harmaline-Induced test deficits. In mouse liver microsomes, NNC 55-0396 was a less potent inhibitor of harmaline O-demethylation than mibefradil (Ki: 0.95 and 0.29 μM respectively), and also less potent at inhibiting testosterone 6-β-hydroxylation (Ki: 0.71 and 0.12 μM respectively). In the GABAA α1-null model, NNC 55-0396 but not mibefradil, (each at 20 mg/kg), suppressed Tremor while NNC 55-0396 at 12.5 mg/kg suppressed Harmaline-Induced Tremor by half by 20–100 min, whereas mibefradil at the same dose did not significantly affect Tremor. In contrast to mibefradil, NNC 55-0396 is well tolerated and suppresses Tremor, and exerts less cytochrome P450 inhibition. These results suggest potential clinical utility for NNC 55-0396 or similar derivatives as a T-type calcium antagonist.
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T-type calcium channel antagonists suppress Tremor in two mouse models of essential Tremor.
Neuropharmacology, 2010Co-Authors: Adrian Handforth, Jae Yeol Lee, Gregg E. Homanics, Douglas F. Covey, Kathiresan Krishnan, Kenji Sakimura, Fredricka C. Martin, Arnulfo QuesadaAbstract:Essential Tremor is a common disorder that lacks molecular targets for therapeutic development. T-type calcium channel activation has been postulated to underlie rhythmicity in the olivo-cerebellar system that is implicated in essential Tremor. We therefore tested whether compounds that antagonize T-type calcium channel currents suppress Tremor in two mouse models that possess an essential Tremor-like pharmacological response profile. Tremor was measured using digitized spectral motion power analysis with Harmaline-Induced Tremor and in the GABA(A) receptor α1 subunit-null model. Mice were given ethosuximide, zonisamide, the neuroactive steroid (3β,5α,17β)-17-hydroxyestrane-3-carbonitrile (ECN), the 3,4-dihydroquinazoline derivative KYS05064, the mibefradil derivative NNC 55-0396, or vehicle. In non-sedating doses, each compound reduced Harmaline-Induced Tremor by at least 50% (range of maximal suppression: 53-81%), and in the GABA(A) α1-null model by at least 70% (range 70-93%). Because the T-type calcium channel Cav3.1 is the dominant subtype expressed in the inferior olive, we assessed the Tremor response of Cav3.1-deficient mice to harmaline, and found that null and heterozygote mice exhibit as much Tremor as wild-type mice. In addition, ECN and NNC 55-0396 suppressed harmaline Tremor as well in Cav3.1-null mice as in wild-type mice. The finding that five T-type calcium antagonists suppress Tremor in two animal Tremor models suggests that T-type calcium channels may be an appropriate target for essential Tremor therapy development. It is uncertain whether medications developed to block only the Cav3.1 subtype would exhibit efficacy.
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Harmaline-Induced Tremor as a potential preclinical screening method for essential Tremor medications.
Movement disorders : official journal of the Movement Disorder Society, 2005Co-Authors: Fredricka C. Martin, Adrian HandforthAbstract:No preclinical method to evaluate potential new medications for essential Tremor (ET) is available currently. Although harmaline Tremor is a well known animal model of ET, it has not found utility as a preclinical drug screen and has not been validated with anti-ET medications. We measured harmaline Tremor in rats (10 mg/kg s.c.) and mice (20 mg/kg s.c.) with a load sensor under the cage floor and performed spectral analysis on 20-minute epochs. The motion power over the Tremor frequency bandwidth (8-12 Hz in rats; 10-16 Hz in mice) was divided by the motion power over the full motion frequency range (0-15 Hz in rats; 0-34 Hz in mice). The use of these measures greatly reduced data variability, permitting experiments with small sample sizes. Three drugs that suppress ET (propranolol, ethanol, and octanol) all significantly suppressed Harmaline-Induced Tremor. We propose that, with this methodology, Harmaline-Induced Tremor may be useful as a preclinical method to identify potential medications for ET.
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Vagus nerve stimulation inhibits Harmaline-Induced Tremor.
Brain research, 2004Co-Authors: Scott E. Krahl, Fredricka C. Martin, Adrian HandforthAbstract:Excessive olivo-cerebellar burst-firing occurs during Harmaline-Induced Tremor. This system receives rich sensory inputs, including visceral. We hypothesized that electrical vagus nerve stimulation (VNS) would suppress harmaline Tremor, as measured with digitized motion power in the rat. Cervical vagus nerve stimulation suppressed power in the 8-12-Hz Tremor range by 40%, whereas sham stimulation was ineffective. This study raises the possibility that activation of various sensory modalities, as well as visceral, may reduce Tremor.
Krystyna Ossowska - One of the best experts on this subject based on the ideXlab platform.
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Pramipexole Reduces zif-268 mRNA Expression in Brain Structures involved in the Generation of Harmaline-Induced Tremor
Neurochemical Research, 2020Co-Authors: Barbara Kosmowska, Krystyna Ossowska, Jadwiga WardasAbstract: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.
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Tremorolytic effect of 5'-chloro-5'-deoxy-(±)-ENBA, a potent and selective adenosine A1 receptor agonist, evaluated in the Harmaline-Induced model in rats.
CNS neuroscience & therapeutics, 2017Co-Authors: Barbara Kosmowska, Krystyna Ossowska, Urszula Głowacka, Jadwiga WardasAbstract:AIM 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. METHODS Harmaline was injected at a dose of 15 mg/kg ip and Tremor was measured automatically in force-plate actimeters by an increased averaged power in the frequency band of 9-15 Hz (AP2) and by Tremor index (a difference in power between AP2 and averaged power in the frequency band of 0-8 Hz). The zif-268 mRNA expression was additionally analyzed by in situ hybridization in several brain structures. RESULTS 5'Cl5'd-(±)-ENBA (0.05-0.5 mg/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 (1 mg/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. CONCLUSION This study suggests that adenosine A1 receptors may be a potential target for the treatment of essential Tremor.
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Pramipexole at a Low Dose Induces Beneficial Effect in the Harmaline‐induced Model of Essential Tremor in Rats
CNS neuroscience & therapeutics, 2015Co-Authors: Barbara Kosmowska, Jadwiga Wardas, Urszula Głowacka, Subramaniam Ananthan, Krystyna OssowskaAbstract:Summary Aims 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. Methods For Tremor measurement, fully automated force plate actimeters were used and data were analyzed using fast Fourier transform. Results 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. Conclusion 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.
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Apomorphine enhances Harmaline-Induced Tremor in rats
Pharmacological Reports, 2015Co-Authors: Krystyna Ossowska, Barbara Kosmowska, Urszula Głowacka, Jadwiga WardasAbstract:Background Harmaline-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. Methods Tremor, 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. Results The Tremor induced by harmaline administered at a dose of 15 mg/kg ip was associated with an increase in power in the 9–15 Hz band (AP2) and in the Tremor index, calculated as a difference between AP2 and power in the 0–8 Hz band (AP1). Propranolol injected at a dose of 20 mg/kg ip reversed both of these effects of harmaline. Apomorphine administered at the doses of 0.5 and 1 mg/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. Conclusions The present study suggests that the dopamine agonist apomorphine enhances the Tremor induced by harmaline, and this effect is at least partly independent of hyperactivity.
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Lu AF21934, a positive allosteric modulator of mGlu4 receptors, reduces the Harmaline-Induced hyperactivity but not Tremor in rats.
Neuropharmacology, 2014Co-Authors: Krystyna Ossowska, Katarzyna Kuter, Jadwiga Wardas, Urszula Głowacka, Klemencja Berghauzen-maciejewska, Andrzej Pilc, Stevin H. Zorn, Dario DollerAbstract:Abstract 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.
Hideto Miwa - One of the best experts on this subject based on the ideXlab platform.
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Rodent models of Tremor
The Cerebellum, 2007Co-Authors: Hideto MiwaAbstract:This review focuses on rodent models of Tremor, particularly those induced by pharmacological agents. Harmaline is one of the most frequently used Tremor-generating drugs and Harmaline-Induced Tremor is regarded as a model of essential Tremor. Harmaline acts on inferior olive neurons, causing enhanced neuronal synchrony and rhythmicity in the olivocerebellar system. In addition, it selectively induces cerebellar Purkinje cell death, speculatively because of excessive glutamate release from nerve terminals of the olivocerebellar system onto Purkinje cells. Systemic administration of cholinomimetics can also produce generalized Tremor, and muscarinic receptors on striatal neurons are thought to be the best candidate for the Tremor-generating mechanism. On the other hand, dopaminergic neurotoxins, which are used in models of parkinsonism, have yet to be used for experimental analysis of Tremor, because Tremors induced by dopamine depletion in rodents are less remarkable than those induced by harmaline or cholinomimetics. Recently developed gamma-aminobutyric acid (GABA) (A) receptor alpha-1 subunit knockout mice exhibit postural and kinetic Tremors, and clearly reproduce the features of essential Tremors. Although from a phenomenological point of view, rodent models of Tremor cannot entirely mimic human Tremor disorders, they have useful advantages in the analysis of pathophysiological mechanisms underlying Tremor. Development of convenient and reproducible methods for evaluating rodent Tremor is therefore recommended.
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A species-specific difference in the effects of harmaline on the rodent olivocerebellar system
Brain research, 2006Co-Authors: Hideto Miwa, Tomomi Kubo, Ai Suzuki, Tameko Kihira, Tomoyoshi KondoAbstract:The rodent model of Harmaline-Induced Tremor has been widely used for experimental analysis of Tremor. Activation of the olivocerebellar system plays a key role in Tremor-generating mechanisms. One undetermined problem is whether there are species-specific differences in effects of harmaline. The present study investigated effects of harmaline on olivocerebellar systems of mice and rats. Systemic administration of harmaline, but not vehicle, produced generalized, high-frequency Tremors in both types of rodents. Immunohistochemical studies revealed significant degeneration of Purkinje cells that was associated with activated microgliosis in the cerebellar cortex, following administration of harmaline in rats but not in mice. However, in mice but not rats, microgliosis was induced following administration of harmaline in the inferior olivary nucleus (ION), particularly in its caudal and medial subdivisions. Numbers of neurons in the mouse ION did not decrease, suggesting the possibility that microgliosis in ION might not be a simple neurotoxic effect. Presumably, differences in sensitivity of Purkinje cells between rats and mice may be related to differences in functional alterations in their respective olivocerebellar systems induced by harmaline. Recognition of these species-specific differences in the response of the olivocerebellar system to harmaline is an important consideration for experimental analysis of the rodent model of Tremors.
Jadwiga Wardas - One of the best experts on this subject based on the ideXlab platform.
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Pramipexole Reduces zif-268 mRNA Expression in Brain Structures involved in the Generation of Harmaline-Induced Tremor
Neurochemical Research, 2020Co-Authors: Barbara Kosmowska, Krystyna Ossowska, Jadwiga WardasAbstract: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.
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Tremorolytic effect of 5'-chloro-5'-deoxy-(±)-ENBA, a potent and selective adenosine A1 receptor agonist, evaluated in the Harmaline-Induced model in rats.
CNS neuroscience & therapeutics, 2017Co-Authors: Barbara Kosmowska, Krystyna Ossowska, Urszula Głowacka, Jadwiga WardasAbstract:AIM 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. METHODS Harmaline was injected at a dose of 15 mg/kg ip and Tremor was measured automatically in force-plate actimeters by an increased averaged power in the frequency band of 9-15 Hz (AP2) and by Tremor index (a difference in power between AP2 and averaged power in the frequency band of 0-8 Hz). The zif-268 mRNA expression was additionally analyzed by in situ hybridization in several brain structures. RESULTS 5'Cl5'd-(±)-ENBA (0.05-0.5 mg/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 (1 mg/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. CONCLUSION This study suggests that adenosine A1 receptors may be a potential target for the treatment of essential Tremor.
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Pramipexole at a Low Dose Induces Beneficial Effect in the Harmaline‐induced Model of Essential Tremor in Rats
CNS neuroscience & therapeutics, 2015Co-Authors: Barbara Kosmowska, Jadwiga Wardas, Urszula Głowacka, Subramaniam Ananthan, Krystyna OssowskaAbstract:Summary Aims 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. Methods For Tremor measurement, fully automated force plate actimeters were used and data were analyzed using fast Fourier transform. Results 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. Conclusion 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.
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Apomorphine enhances Harmaline-Induced Tremor in rats
Pharmacological Reports, 2015Co-Authors: Krystyna Ossowska, Barbara Kosmowska, Urszula Głowacka, Jadwiga WardasAbstract:Background Harmaline-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. Methods Tremor, 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. Results The Tremor induced by harmaline administered at a dose of 15 mg/kg ip was associated with an increase in power in the 9–15 Hz band (AP2) and in the Tremor index, calculated as a difference between AP2 and power in the 0–8 Hz band (AP1). Propranolol injected at a dose of 20 mg/kg ip reversed both of these effects of harmaline. Apomorphine administered at the doses of 0.5 and 1 mg/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. Conclusions The present study suggests that the dopamine agonist apomorphine enhances the Tremor induced by harmaline, and this effect is at least partly independent of hyperactivity.
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Lu AF21934, a positive allosteric modulator of mGlu4 receptors, reduces the Harmaline-Induced hyperactivity but not Tremor in rats.
Neuropharmacology, 2014Co-Authors: Krystyna Ossowska, Katarzyna Kuter, Jadwiga Wardas, Urszula Głowacka, Klemencja Berghauzen-maciejewska, Andrzej Pilc, Stevin H. Zorn, Dario DollerAbstract:Abstract 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.
Su Youne Chang - One of the best experts on this subject based on the ideXlab platform.
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Altered Primary Motor Cortex Neuronal Activity in a Rat Model of Harmaline-Induced Tremor During Thalamic Deep Brain Stimulation.
Frontiers in cellular neuroscience, 2019Co-Authors: Jihyun Lee, Su Youne ChangAbstract:Although deep brain stimulation (DBS) is clinically effective surgical treatment for essential Tremor (ET), its neurophysiological mechanisms are not fully understood. Since the ventrolateral (VL) thalamus is the most popular DBS target for ET and it is known that thalamic nucleus plays a key role in relaying information about the external environment to the cerebral cortex, it is important to investigate mechanisms of thalamic DBS in the context of cerebello-thalamo-cortical neuronal network. To examine this, we measured single-unit neuronal activities in the resting state in M1 during VL thalamic DBS in the Harmaline-Induced Tremor rats and analyzed neuronal activity patterns in the thalamo-cortical circuit. Four activity patterns, such as oscillatory burst, oscillatory non-burst, irregular burst and irregular non-burst, were identified by harmaline administration and those firing patterns were differentially affected by VL thalamic DBS, which seems to drive pathologic cortical signals to signals in normal status. Since specific neuronal firing patterns like oscillation or burst are considered important for information processing, our results suggest that VL thalamic DBS may modify pathophysiologic relay information rather than simply inhibit the information transmission.
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Mapping BOLD Activation by Pharmacologically Evoked Tremor in Swine
Frontiers in neuroscience, 2019Co-Authors: Jeyeon Lee, Jihyun Lee, Inyong Kim, Emily J. Knight, Hoon Ki Min, Su Youne ChangAbstract:Harmaline-Induced Tremor is one of the most commonly utilized disease models for essential Tremor (ET). However, the underlying neural networks involved in Harmaline-Induced Tremor and the degree to which these are a representative model of the pathophysiologic mechanism of ET are incompletely understood. In this study, we evaluated the functional brain network effects induced by systemic injection of harmaline using pharmacological functional magnetic resonance imaging (ph-fMRI) in the swine model. With harmaline administration, we observed significant activation changes in cerebellum, thalamus, and inferior olivary nucleus (ION). In addition, inter-regional correlations in activity between cerebellum and deep cerebellar nuclei and between cerebellum and thalamus were significantly enhanced. These Harmaline-Induced effects gradually decreased with repeated administration of drug, replicating the previously demonstrated 'tolerance' effect. This study demonstrates that Harmaline-Induced Tremor is associated with activity changes in brain regions previously implicated in humans with ET. Thus, harmaline-induction of Tremor in the swine may be a useful model to explore the neurological effects of novel therapeutic agents and/or neuromodulation techniques for ET.
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Development of Harmaline-Induced Tremor in a Swine Model
Tremor and other hyperkinetic movements (New York N.Y.), 2018Co-Authors: Jihyun Lee, Inyong Kim, Jeyeon Lee, Emily J. Knight, Lei Cheng, Shin Il Kang, Dong Pyo Jang, Su Youne ChangAbstract:Background: In the field of translational neuroscience research, it is critical to utilize a large animal model to test the feasibility, safety, and functionality of novel therapies. Here, we describe a protocol for the development of a large animal model of Tremor. Methods: In a pig model, Tremor was induced with harmaline and measured with wireless accelerometers attached to the limbs. Three different doses of harmaline were tested and three repetitive injections were made at 72-hour intervals. To fully characterize the drug-induced Tremor, onset time, Tremor amplitude, maintained duration, and peak Tremor frequency were analyzed. Results: Harmaline-Induced Tremor appeared immediately following intravenous injection of harmaline. Tremor was maintained over 2 hours. Its frequency was 10–16 Hz, which was independent of doses. Dose-dependent responses were observed in Tremor amplitude, triggering time, and Tremor-maintained duration. Repetitive injection of harmaline desensitized the harmaline effect. Discussion: We provide a detailed protocol for training, drug injection, device selection, and Tremor recording optimized to create a swine model of Tremor with harmaline. Our protocol provides reliable Tremor in pigs and suggests pig as a valid translational large animal model of Tremor.
