Dopamine receptor agonists reverse behavioral abnormalities of α‐synuclein transgenic mouse, a new model of Parkinson's disease
Identifieur interne : 002056 ( Main/Corpus ); précédent : 002055; suivant : 002057Dopamine receptor agonists reverse behavioral abnormalities of α‐synuclein transgenic mouse, a new model of Parkinson's disease
Auteurs : Masaki Wakamatsu ; Shingo Iwata ; Takeo Funakoshi ; Makoto YoshimotoSource :
- Journal of Neuroscience Research [ 0360-4012 ] ; 2008-02-15.
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- KwdEn :
Abstract
Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human α‐synuclein (amino acid residues 1–130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L‐DOPA and DA receptor agonists. Administration of L‐DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D2 agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non‐Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D2‐like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease. © 2007 Wiley‐Liss, Inc.
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DOI: 10.1002/jnr.21513
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Res.</title><idno type="ISSN">0360-4012</idno><idno type="eISSN">1097-4547</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2008-02-15">2008-02-15</date><biblScope unit="volume">86</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="640">640</biblScope><biblScope unit="page" to="646">646</biblScope></imprint><idno type="ISSN">0360-4012</idno></series><idno type="istex">929D3A05B7BCCEFE3C10004E50DE3E6C7FC3366D</idno><idno type="DOI">10.1002/jnr.21513</idno><idno type="ArticleID">JNR21513</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0360-4012</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>L‐DOPA</term><term>Parkinson's disease</term><term>dopaminergic neuron</term><term>locomotor activity</term><term>pergolide</term><term>tali‐pexole</term><term>transgenic mouse</term><term>α‐synuclein</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human α‐synuclein (amino acid residues 1–130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L‐DOPA and DA receptor agonists. Administration of L‐DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D2 agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non‐Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D2‐like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease. © 2007 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Masaki Wakamatsu</name><affiliations><json:string>Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Shingo Iwata</name><affiliations><json:string>Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Takeo Funakoshi</name><affiliations><json:string>Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item><json:item><name>Makoto Yoshimoto</name><affiliations><json:string>Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>α‐synuclein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>transgenic mouse</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopaminergic neuron</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>L‐DOPA</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pergolide</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>tali‐pexole</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>locomotor activity</value></json:item></subject><articleId><json:string>JNR21513</json:string></articleId><language><json:string>eng</json:string></language><abstract>Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human α‐synuclein (amino acid residues 1–130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L‐DOPA and DA receptor agonists. Administration of L‐DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D2 agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non‐Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D2‐like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. 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We had previously generated transgenic mice termed Syn130m that express truncated human α‐synuclein (amino acid residues 1–130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L‐DOPA and DA receptor agonists. Administration of L‐DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D2 agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non‐Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D2‐like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease. © 2007 Wiley‐Liss, Inc.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>Parkinson's disease</term></item><item><term>α‐synuclein</term></item><item><term>transgenic mouse</term></item><item><term>dopaminergic neuron</term></item><item><term>L‐DOPA</term></item><item><term>pergolide</term></item><item><term>tali‐pexole</term></item><item><term>locomotor activity</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2007-06-27">Received</change><change when="2007-07-19">Registration</change><change when="2008-02-15">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/929D3A05B7BCCEFE3C10004E50DE3E6C7FC3366D/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1097-4547</doi><issn type="print">0360-4012</issn><issn type="electronic">1097-4547</issn><idGroup><id type="product" value="JNR"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="JOURNAL OF NEUROSCIENCE RESEARCH">Journal of Neuroscience Research</title><title type="short">J. 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We had previously generated transgenic mice termed <i>Syn130m</i> that express truncated human α‐synuclein (amino acid residues 1–130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L‐DOPA and DA receptor agonists. Administration of L‐DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D<sub>2</sub> agonists, quinpirole and talipexole, and a D<sub>1</sub>/D<sub>2</sub> agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non‐Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D<sub>2</sub>‐like receptors (DRD<sub>2</sub>) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD<sub>2</sub>. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease. © 2007 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Dopamine receptor agonists reverse behavioral abnormalities of α‐synuclein transgenic mouse, a new model of Parkinson's disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>New Mouse Model of Parkinson's Disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Dopamine receptor agonists reverse behavioral abnormalities of α‐synuclein transgenic mouse, a new model of Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Masaki</namePart><namePart type="family">Wakamatsu</namePart><affiliation>Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shingo</namePart><namePart type="family">Iwata</namePart><affiliation>Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Takeo</namePart><namePart type="family">Funakoshi</namePart><affiliation>Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Makoto</namePart><namePart type="family">Yoshimoto</namePart><affiliation>Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan</affiliation><description>Correspondence: Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Yoshino‐cho 1‐403, Kita‐ku, Saitama‐shi, Saitama, 331‐9530, Japan</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2008-02-15</dateIssued><dateCaptured encoding="w3cdtf">2007-06-27</dateCaptured><dateValid encoding="w3cdtf">2007-07-19</dateValid><copyrightDate encoding="w3cdtf">2008</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">4</extent><extent unit="references">44</extent><extent unit="words">4646</extent></physicalDescription><abstract lang="en">Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is α‐synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human α‐synuclein (amino acid residues 1–130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L‐DOPA and DA receptor agonists. Administration of L‐DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D2 agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non‐Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D2‐like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease. © 2007 Wiley‐Liss, Inc.</abstract><note type="funding">Taisho Pharmaceutical Co., Ltd.</note><subject lang="en"><genre>Keywords</genre><topic>Parkinson's disease</topic><topic>α‐synuclein</topic><topic>transgenic mouse</topic><topic>dopaminergic neuron</topic><topic>L‐DOPA</topic><topic>pergolide</topic><topic>tali‐pexole</topic><topic>locomotor activity</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Neuroscience Research</title></titleInfo><titleInfo type="abbreviated"><title>J. Neurosci. Res.</title></titleInfo><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0360-4012</identifier><identifier type="eISSN">1097-4547</identifier><identifier type="DOI">10.1002/(ISSN)1097-4547</identifier><identifier type="PublisherID">JNR</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>86</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>640</start><end>646</end><total>7</total></extent></part></relatedItem><identifier type="istex">929D3A05B7BCCEFE3C10004E50DE3E6C7FC3366D</identifier><identifier type="DOI">10.1002/jnr.21513</identifier><identifier type="ArticleID">JNR21513</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2007 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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