Gene knockout approach to adenosine A2A receptors in Parkinson's disease
Identifieur interne : 000A83 ( Main/Corpus ); précédent : 000A82; suivant : 000A84Gene knockout approach to adenosine A2A receptors in Parkinson's disease
Auteurs : Jiang-Fan Chen ; Michael A. SchwarzschildSource :
- Drug Development Research [ 0272-4391 ] ; 2003-04.
English descriptors
- KwdEn :
Abstract
Recently, the adenosine A2A receptor (A2AR) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D2 receptor (D2R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A2AR and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A2ARs and D2Rs overcome some of the intrinsic limitations of A2A antagonists and provide an opportunity to investigate A2AR's role in the development and treatment of PD. First, we used D2 as well as A2AR KO mice to dissect the molecular mechanism of the A2AR's action by determining the dependence of A2AR function on D2 receptors. The A2A antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D2 receptor. These results suggest that A2AR antagonists enhance motor function at least partially independent of D2 receptors. Second, we explored the role of A2ARs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A2ARs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A2AR plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A2ARs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A2AR inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D2‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A2A KO mouse models will further refine our understanding of the A2A receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.
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DOI: 10.1002/ddr.10215
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Gene knockout approach to adenosine A2A receptors in Parkinson's disease</title><author><name sortKey="Chen, Jiang An" sort="Chen, Jiang An" uniqKey="Chen J" first="Jiang-Fan" last="Chen">Jiang-Fan Chen</name><affiliation><mods:affiliation>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</mods:affiliation></affiliation><affiliation><mods:affiliation>Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts</mods:affiliation></affiliation></author><author><name sortKey="Schwarzschild, Michael A" sort="Schwarzschild, Michael A" uniqKey="Schwarzschild M" first="Michael A." last="Schwarzschild">Michael A. Schwarzschild</name><affiliation><mods:affiliation>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:DAAD0DB044213BD3BAF55552E4BE3843E7ADE242</idno><date when="2003" year="2003">2003</date><idno type="doi">10.1002/ddr.10215</idno><idno type="url">https://api.istex.fr/document/DAAD0DB044213BD3BAF55552E4BE3843E7ADE242/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000A83</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Gene knockout approach to adenosine A2A receptors in Parkinson's disease</title><author><name sortKey="Chen, Jiang An" sort="Chen, Jiang An" uniqKey="Chen J" first="Jiang-Fan" last="Chen">Jiang-Fan Chen</name><affiliation><mods:affiliation>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</mods:affiliation></affiliation><affiliation><mods:affiliation>Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts</mods:affiliation></affiliation></author><author><name sortKey="Schwarzschild, Michael A" sort="Schwarzschild, Michael A" uniqKey="Schwarzschild M" first="Michael A." last="Schwarzschild">Michael A. 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Res.</title><idno type="ISSN">0272-4391</idno><idno type="eISSN">1098-2299</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2003-04">2003-04</date><biblScope unit="volume">58</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="354">354</biblScope><biblScope unit="page" to="367">367</biblScope></imprint><idno type="ISSN">0272-4391</idno></series><idno type="istex">DAAD0DB044213BD3BAF55552E4BE3843E7ADE242</idno><idno type="DOI">10.1002/ddr.10215</idno><idno type="ArticleID">DDR10215</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0272-4391</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson's disease</term><term>adenosine A2A antagonist</term><term>adenosine A2A receptor</term><term>caffeine</term><term>dopamine D2 receptor</term><term>gene knockout</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Recently, the adenosine A2A receptor (A2AR) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D2 receptor (D2R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A2AR and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A2ARs and D2Rs overcome some of the intrinsic limitations of A2A antagonists and provide an opportunity to investigate A2AR's role in the development and treatment of PD. First, we used D2 as well as A2AR KO mice to dissect the molecular mechanism of the A2AR's action by determining the dependence of A2AR function on D2 receptors. The A2A antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D2 receptor. These results suggest that A2AR antagonists enhance motor function at least partially independent of D2 receptors. Second, we explored the role of A2ARs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A2ARs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A2AR plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A2ARs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A2AR inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D2‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A2A KO mouse models will further refine our understanding of the A2A receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Jiang‐Fan Chen</name><affiliations><json:string>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</json:string><json:string>Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts</json:string></affiliations></json:item><json:item><name>Michael A. Schwarzschild</name><affiliations><json:string>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>adenosine A2A receptor</value></json:item><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>gene knockout</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>caffeine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>adenosine A2A antagonist</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopamine D2 receptor</value></json:item></subject><articleId><json:string>DDR10215</json:string></articleId><language><json:string>eng</json:string></language><abstract>Recently, the adenosine A2A receptor (A2AR) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D2 receptor (D2R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A2AR and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A2ARs and D2Rs overcome some of the intrinsic limitations of A2A antagonists and provide an opportunity to investigate A2AR's role in the development and treatment of PD. First, we used D2 as well as A2AR KO mice to dissect the molecular mechanism of the A2AR's action by determining the dependence of A2AR function on D2 receptors. The A2A antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D2 receptor. These results suggest that A2AR antagonists enhance motor function at least partially independent of D2 receptors. Second, we explored the role of A2ARs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A2ARs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A2AR plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A2ARs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A2AR inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D2‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A2A KO mouse models will further refine our understanding of the A2A receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.</abstract><qualityIndicators><score>8</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595 x 791 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>2621</abstractCharCount><pdfWordCount>9154</pdfWordCount><pdfCharCount>60409</pdfCharCount><pdfPageCount>14</pdfPageCount><abstractWordCount>372</abstractWordCount></qualityIndicators><title>Gene knockout approach to adenosine A2A receptors in Parkinson's disease</title><genre><json:string>article</json:string></genre><host><volume>58</volume><publisherId><json:string>DDR</json:string></publisherId><pages><total>14</total><last>367</last><first>354</first></pages><issn><json:string>0272-4391</json:string></issn><issue>4</issue><author><json:item><name>John Headrick</name></json:item></author><subject><json:item><value>Research Overview</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1098-2299</json:string></eissn><title>Drug Development Research</title><doi><json:string>10.1002/(ISSN)1098-2299</json:string></doi></host><publicationDate>2003</publicationDate><copyrightDate>2003</copyrightDate><doi><json:string>10.1002/ddr.10215</json:string></doi><id>DAAD0DB044213BD3BAF55552E4BE3843E7ADE242</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/DAAD0DB044213BD3BAF55552E4BE3843E7ADE242/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/DAAD0DB044213BD3BAF55552E4BE3843E7ADE242/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/DAAD0DB044213BD3BAF55552E4BE3843E7ADE242/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Gene knockout approach to adenosine A2A receptors in Parkinson's disease</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2003</date></publicationStmt><notesStmt><note>NIH - No. NS41083; No. NS37403; No. DA13508;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Gene knockout approach to adenosine A2A receptors in Parkinson's disease</title><author><persName><forename type="first">Jiang‐Fan</forename><surname>Chen</surname></persName><note type="correspondence"><p>Correspondence: Department of Neurology, Boston University School of Medicine, 715 Albany Street, C314, Boston, MA 02118</p></note><affiliation>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</affiliation><affiliation>Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts</affiliation></author><author><persName><forename type="first">Michael A.</forename><surname>Schwarzschild</surname></persName><affiliation>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</affiliation></author></analytic><monogr><title level="j">Drug Development Research</title><title level="j" type="abbrev">Drug Dev. Res.</title><idno type="pISSN">0272-4391</idno><idno type="eISSN">1098-2299</idno><idno type="DOI">10.1002/(ISSN)1098-2299</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2003-04"></date><biblScope unit="volume">58</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="354">354</biblScope><biblScope unit="page" to="367">367</biblScope></imprint></monogr><idno type="istex">DAAD0DB044213BD3BAF55552E4BE3843E7ADE242</idno><idno type="DOI">10.1002/ddr.10215</idno><idno type="ArticleID">DDR10215</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2003</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Recently, the adenosine A2A receptor (A2AR) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D2 receptor (D2R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A2AR and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A2ARs and D2Rs overcome some of the intrinsic limitations of A2A antagonists and provide an opportunity to investigate A2AR's role in the development and treatment of PD. First, we used D2 as well as A2AR KO mice to dissect the molecular mechanism of the A2AR's action by determining the dependence of A2AR function on D2 receptors. The A2A antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D2 receptor. These results suggest that A2AR antagonists enhance motor function at least partially independent of D2 receptors. Second, we explored the role of A2ARs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A2ARs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A2AR plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A2ARs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A2AR inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D2‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A2A KO mouse models will further refine our understanding of the A2A receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>adenosine A2A receptor</term></item><item><term>Parkinson's disease</term></item><item><term>gene knockout</term></item><item><term>caffeine</term></item><item><term>adenosine A2A antagonist</term></item><item><term>dopamine D2 receptor</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Research Overview</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2003-04">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/DAAD0DB044213BD3BAF55552E4BE3843E7ADE242/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)1098-2299</doi><issn type="print">0272-4391</issn><issn type="electronic">1098-2299</issn><idGroup><id type="product" value="DDR"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="DRUG DEVELOPMENT RESEARCH">Drug Development Research</title><title type="short">Drug Dev. Res.</title></titleGroup></publicationMeta><publicationMeta level="part" position="40"><doi origin="wiley" registered="yes">10.1002/ddr.v58:4</doi><titleGroup><title type="specialIssueTitle">Proceedings of the Seventh International Symposium on Adenosine and Adenine Nucleotides ‐ Part 1</title></titleGroup><numberingGroup><numbering type="journalVolume" number="58">58</numbering><numbering type="journalIssue">4</numbering></numberingGroup><creators><creator xml:id="sped1" creatorRole="sponsoringEditor"><personName><givenNames>John</givenNames><familyName>Headrick</familyName></personName></creator></creators><coverDate startDate="2003-04">April 2003</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="9" status="forIssue"><doi origin="wiley" registered="yes">10.1002/ddr.10215</doi><idGroup><id type="unit" value="DDR10215"></id></idGroup><countGroup><count type="pageTotal" number="14"></count></countGroup><titleGroup><title type="articleCategory">Research Overview</title><title type="tocHeading1">Research Overview</title></titleGroup><copyright ownership="publisher">© 2003 Wiley‐Liss, Inc.</copyright><eventGroup><event type="firstOnline" date="2003-05-22"></event><event type="publishedOnlineFinalForm" date="2003-05-22"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.2 mode:FullText source:HeaderRef result:HeaderRef" date="2010-03-06"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-17"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-16"></event></eventGroup><numberingGroup><numbering type="pageFirst">354</numbering><numbering type="pageLast">367</numbering></numberingGroup><correspondenceTo>Department of Neurology, Boston University School of Medicine, 715 Albany Street, C314, Boston, MA 02118</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:DDR.DDR10215.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="4"></count><count type="tableTotal" number="0"></count><count type="referenceTotal" number="129"></count></countGroup><titleGroup><title type="main" xml:lang="en">Gene knockout approach to adenosine A<sub>2A</sub> receptors in Parkinson's disease</title><title type="short" xml:lang="en">GENETIC APPROACH TO A<sub>2A</sub> RECEPTORS IN PD</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>Jiang‐Fan</givenNames><familyName>Chen</familyName></personName><contactDetails><email>chenjf@bu.edu</email></contactDetails></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Michael A.</givenNames><familyName>Schwarzschild</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">adenosine A<sub>2A</sub> receptor</keyword><keyword xml:id="kwd2">Parkinson's disease</keyword><keyword xml:id="kwd3">gene knockout</keyword><keyword xml:id="kwd4">caffeine</keyword><keyword xml:id="kwd5">adenosine A<sub>2A</sub> antagonist</keyword><keyword xml:id="kwd6">dopamine D<sub>2</sub> receptor</keyword></keywordGroup><fundingInfo><fundingAgency>NIH</fundingAgency><fundingNumber>NS41083</fundingNumber><fundingNumber>NS37403</fundingNumber><fundingNumber>DA13508</fundingNumber></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Recently, the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D<sub>2</sub> receptor (D<sub>2</sub>R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A<sub>2A</sub>R and D<sub>2</sub>R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A<sub>2A</sub>Rs and D<sub>2</sub>Rs overcome some of the intrinsic limitations of A<sub>2A</sub> antagonists and provide an opportunity to investigate A<sub>2A</sub>R's role in the development and treatment of PD. First, we used D<sub>2</sub> as well as A<sub>2A</sub>R KO mice to dissect the molecular mechanism of the A<sub>2A</sub>R's action by determining the dependence of A<sub>2A</sub>R function on D<sub>2</sub> receptors. The A<sub>2A</sub> antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D<sub>2</sub> receptor. These results suggest that A<sub>2A</sub>R antagonists enhance motor function at least partially independent of D<sub>2</sub> receptors. Second, we explored the role of A<sub>2A</sub>Rs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A<sub>2A</sub>Rs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A<sub>2A</sub>R plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A<sub>2A</sub>Rs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A<sub>2A</sub>R inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D<sub>2</sub>‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A<sub>2A</sub> KO mouse models will further refine our understanding of the A<sub>2A</sub> receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Gene knockout approach to adenosine A2A receptors in Parkinson's disease</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>GENETIC APPROACH TO A2A RECEPTORS IN PD</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Gene knockout approach to adenosine A</title></titleInfo><name type="personal"><namePart type="given">Jiang‐Fan</namePart><namePart type="family">Chen</namePart><affiliation>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</affiliation><affiliation>Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts</affiliation><description>Correspondence: Department of Neurology, Boston University School of Medicine, 715 Albany Street, C314, Boston, MA 02118</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael A.</namePart><namePart type="family">Schwarzschild</namePart><affiliation>Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts</affiliation><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">2003-04</dateIssued><copyrightDate encoding="w3cdtf">2003</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">129</extent></physicalDescription><abstract lang="en">Recently, the adenosine A2A receptor (A2AR) has emerged as an attractive target for Parkinson's disease (PD) treatment by virtue of its coexpression with the dopamine D2 receptor (D2R) in the striatum and its modulation of dopamine receptor‐mediated functions. Moreover, the adenosine antagonist, caffeine, has recently been linked to a reduced risk of developing PD in large prospective epidemiological studies, raising the possibility that caffeine and more specific adenosine antagonists may protect against dopaminergic neuron death. Recently, we and others have developed a series of A2AR and D2R knockout (KO) mouse models. These mutant mouse models with complete, specific genetic inactivation of A2ARs and D2Rs overcome some of the intrinsic limitations of A2A antagonists and provide an opportunity to investigate A2AR's role in the development and treatment of PD. First, we used D2 as well as A2AR KO mice to dissect the molecular mechanism of the A2AR's action by determining the dependence of A2AR function on D2 receptors. The A2A antagonist (CSC) and the nonspecific antagonist caffeine induced motor stimulation in naive and reserpinized mice deficient in D2 receptor. These results suggest that A2AR antagonists enhance motor function at least partially independent of D2 receptors. Second, we explored the role of A2ARs in the development of L‐dopa‐induced behavioral sensitization in unilaterally 6‐hydroxydopamine‐lesioned mice, an animal model of the behavioral and neurochemical features of dyskinesia in PD. Genetic inactivation of A2ARs markedly attenuated the development and persistence of L‐dopa‐induced rotational behavioral sensitization and attenuated induction of dynorphin mRNA in the striatum. The results suggest that A2AR plays a critical role in the development of persistent maladaptive dyskinetic responses to chronic L‐dopa treatment in PD. Finally, we showed that genetic inactivation of A2ARs attenuates MPTP‐induced depletion of dopamine and dopamine transporter (DAT) in the striatum and loss of dopaminergic neurons in the substantia nigra. Together, these results obtained with genetic approaches demonstrate that A2AR inactivation may have multiple therapeutic benefits for PD: motor enhancement through a partial D2‐independent mechanism, prevention of L‐dopa‐induced behavioral sensitization, and attenuation of dopaminergic neurodegeneration. The generation of tissue‐specific and inducible A2A KO mouse models will further refine our understanding of the A2A receptor's role in the development and treatment of PD. Drug Dev. Res. 58:354–367, 2003. © 2003 Wiley‐Liss, Inc.</abstract><note type="funding">NIH - No. NS41083; No. NS37403; No. DA13508; </note><subject lang="en"><genre>Keywords</genre><topic>adenosine A2A receptor</topic><topic>Parkinson's disease</topic><topic>gene knockout</topic><topic>caffeine</topic><topic>adenosine A2A antagonist</topic><topic>dopamine D2 receptor</topic></subject><relatedItem type="host"><titleInfo><title>Drug Development Research</title></titleInfo><titleInfo type="abbreviated"><title>Drug Dev. Res.</title></titleInfo><name type="personal"><namePart type="given">John</namePart><namePart type="family">Headrick</namePart></name><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Research Overview</topic></subject><identifier type="ISSN">0272-4391</identifier><identifier type="eISSN">1098-2299</identifier><identifier type="DOI">10.1002/(ISSN)1098-2299</identifier><identifier type="PublisherID">DDR</identifier><part><date>2003</date><detail type="title"><title>Proceedings of the Seventh International Symposium on Adenosine and Adenine Nucleotides ‐ Part 1</title></detail><detail type="volume"><caption>vol.</caption><number>58</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>354</start><end>367</end><total>14</total></extent></part></relatedItem><identifier type="istex">DAAD0DB044213BD3BAF55552E4BE3843E7ADE242</identifier><identifier type="DOI">10.1002/ddr.10215</identifier><identifier type="ArticleID">DDR10215</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2003 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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