In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD
Identifieur interne : 002676 ( Main/Exploration ); précédent : 002675; suivant : 002677In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD
Auteurs : Vesna Sossi [Canada] ; James E. Holden [États-Unis] ; Geoffrey J. Topping [Canada] ; Marie-Laure Camborde [Canada] ; Rich A. Kornelsen [Canada] ; Siobhan E. Mccormick [Canada] ; Jennifer Greene [Canada] ; Andrei R. Studenov [Canada] ; Thomas J. Ruth [Canada] ; Doris J. Doudet [Canada]Source :
- Journal of cerebral blood flow and metabolism [ 0271-678X ] ; 2007.
Descripteurs français
- Pascal (Inist)
English descriptors
Abstract
This is the first in vivo determination of the vesicular monoamine transporter (VMAT2) density (Bmax) and ligand-transporter affinity (Kappd) in six unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats using micro-positron emission tomography (PET) imaging with [11C]-(+)-α-dihydrotetrabenazine (DTBZ). A multiple ligand concentration transporter assay (MLCTA) was used to determine a Bmax value of 178±32pmol/mL and a Kappd of 47.7±9.3pmol/mL for the non-lesioned side and 30.52±5.84 and 43.4±15.52pmol/mL for the lesioned side, respectively. While Bmax was significantly different between the two sides, no significant difference was observed for the Kappd. In addition to demonstrating the feasibility of in vivo Scatchard analysis in rats, these data confirm the expectation that a 6-OHDA lesion does not affect the affinity; a much simpler binding potential (BP) measure can thus be used as a marker of lesion severity (LS) in this rat model of Parkinson's disease. A transporter occupancy curve demonstrated negligible transporter occupancy (∼1%) at a specific activity (SA) of 1100nCI/pmol (assuming an injected dose of 100μCi/100g), while 10% occupancy was estimated at 100nCi/pmol. An indirect measurement indicated that the degree of occupancy as a function of SA is independent of LS. Finally, BP measurement reproducibility was assessed and found to be 11%±7% for the healthy and 8%±12% for the lesioned side. Quantitative PET results can thus be obtained even for severely lesioned animals with the striatum on one side not clearly visible provided accurate image analysis methods are used.
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Doudet</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Medicine, University of British Columbia</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">08-0028082</idno><date when="2007">2007</date><idno type="stanalyst">PASCAL 08-0028082 INIST</idno><idno type="RBID">Pascal:08-0028082</idno><idno type="wicri:Area/PascalFrancis/Corpus">000683</idno><idno type="wicri:Area/PascalFrancis/Curation">000627</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000646</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000646</idno><idno type="wicri:doubleKey">0271-678X:2007:Sossi V:in:vivo:measurement</idno><idno type="wicri:Area/Main/Merge">002936</idno><idno type="wicri:Area/Main/Curation">002676</idno><idno type="wicri:Area/Main/Exploration">002676</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD</title><author><name sortKey="Sossi, Vesna" sort="Sossi, Vesna" uniqKey="Sossi V" first="Vesna" last="Sossi">Vesna Sossi</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Physics and Astronomy, University of British Columbia</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author><author><name sortKey="Holden, James E" sort="Holden, James E" uniqKey="Holden J" first="James E." last="Holden">James E. Holden</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Medical Physics, University of Wisconsin</s1><s2>Madison, Wisconsin</s2><s3>USA</s3><sZ>2 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Wisconsin</region></placeName></affiliation></author><author><name sortKey="Topping, Geoffrey J" sort="Topping, Geoffrey J" uniqKey="Topping G" first="Geoffrey J." last="Topping">Geoffrey J. Topping</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Physics and Astronomy, University of British Columbia</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author><author><name sortKey="Camborde, Marie Laure" sort="Camborde, Marie Laure" uniqKey="Camborde M" first="Marie-Laure" last="Camborde">Marie-Laure Camborde</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Physics and Astronomy, University of British Columbia</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author><author><name sortKey="Kornelsen, Rich A" sort="Kornelsen, Rich A" uniqKey="Kornelsen R" first="Rich A." last="Kornelsen">Rich A. Kornelsen</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Physics and Astronomy, University of British Columbia</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author><author><name sortKey="Mccormick, Siobhan E" sort="Mccormick, Siobhan E" uniqKey="Mccormick S" first="Siobhan E." last="Mccormick">Siobhan E. Mccormick</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Physics and Astronomy, University of British Columbia</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author><author><name sortKey="Greene, Jennifer" sort="Greene, Jennifer" uniqKey="Greene J" first="Jennifer" last="Greene">Jennifer Greene</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>TRIUMF</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>TRIUMF</wicri:noRegion></affiliation></author><author><name sortKey="Studenov, Andrei R" sort="Studenov, Andrei R" uniqKey="Studenov A" first="Andrei R." last="Studenov">Andrei R. Studenov</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>TRIUMF</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>TRIUMF</wicri:noRegion></affiliation></author><author><name sortKey="Ruth, Thomas J" sort="Ruth, Thomas J" uniqKey="Ruth T" first="Thomas J." last="Ruth">Thomas J. Ruth</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>TRIUMF</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>TRIUMF</wicri:noRegion></affiliation></author><author><name sortKey="Doudet, Doris J" sort="Doudet, Doris J" uniqKey="Doudet D" first="Doris J." last="Doudet">Doris J. Doudet</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Medicine, University of British Columbia</s1><s2>Vancouver</s2><s3>CAN</s3><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Journal of cerebral blood flow and metabolism</title><title level="j" type="abbreviated">J. cereb. blood flow metab.</title><idno type="ISSN">0271-678X</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of cerebral blood flow and metabolism</title><title level="j" type="abbreviated">J. cereb. blood flow metab.</title><idno type="ISSN">0271-678X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal</term><term>Cerebrovascular disease</term><term>Density measurement</term><term>Nervous system diseases</term><term>Rat</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Pathologie du système nerveux</term><term>Pathologie cérébrovasculaire</term><term>Mesure densité</term><term>Animal</term><term>Rat</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">This is the first in vivo determination of the vesicular monoamine transporter (VMAT2) density (B<sub>max</sub>) and ligand-transporter affinity (K<sup>app</sup><sub>d</sub>) in six unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats using micro-positron emission tomography (PET) imaging with [<sup>11</sup>C]-(+)-α-dihydrotetrabenazine (DTBZ). A multiple ligand concentration transporter assay (MLCTA) was used to determine a B<sub>max</sub> value of 178±32pmol/mL and a K<sup>app</sup><sub>d</sub> of 47.7±9.3pmol/mL for the non-lesioned side and 30.52±5.84 and 43.4±15.52pmol/mL for the lesioned side, respectively. While B<sub>max</sub> was significantly different between the two sides, no significant difference was observed for the K<sup>app</sup><sub>d</sub>. In addition to demonstrating the feasibility of in vivo Scatchard analysis in rats, these data confirm the expectation that a 6-OHDA lesion does not affect the affinity; a much simpler binding potential (BP) measure can thus be used as a marker of lesion severity (LS) in this rat model of Parkinson's disease. A transporter occupancy curve demonstrated negligible transporter occupancy (∼1%) at a specific activity (SA) of 1100nCI/pmol (assuming an injected dose of 100μCi/100g), while 10% occupancy was estimated at 100nCi/pmol. An indirect measurement indicated that the degree of occupancy as a function of SA is independent of LS. Finally, BP measurement reproducibility was assessed and found to be 11%±7% for the healthy and 8%±12% for the lesioned side. Quantitative PET results can thus be obtained even for severely lesioned animals with the striatum on one side not clearly visible provided accurate image analysis methods are used.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Wisconsin</li></region></list><tree><country name="Canada"><noRegion><name sortKey="Sossi, Vesna" sort="Sossi, Vesna" uniqKey="Sossi V" first="Vesna" last="Sossi">Vesna Sossi</name></noRegion><name sortKey="Camborde, Marie Laure" sort="Camborde, Marie Laure" uniqKey="Camborde M" first="Marie-Laure" last="Camborde">Marie-Laure Camborde</name><name sortKey="Doudet, Doris J" sort="Doudet, Doris J" uniqKey="Doudet D" first="Doris J." last="Doudet">Doris J. Doudet</name><name sortKey="Greene, Jennifer" sort="Greene, Jennifer" uniqKey="Greene J" first="Jennifer" last="Greene">Jennifer Greene</name><name sortKey="Kornelsen, Rich A" sort="Kornelsen, Rich A" uniqKey="Kornelsen R" first="Rich A." last="Kornelsen">Rich A. Kornelsen</name><name sortKey="Mccormick, Siobhan E" sort="Mccormick, Siobhan E" uniqKey="Mccormick S" first="Siobhan E." last="Mccormick">Siobhan E. Mccormick</name><name sortKey="Ruth, Thomas J" sort="Ruth, Thomas J" uniqKey="Ruth T" first="Thomas J." last="Ruth">Thomas J. Ruth</name><name sortKey="Studenov, Andrei R" sort="Studenov, Andrei R" uniqKey="Studenov A" first="Andrei R." last="Studenov">Andrei R. Studenov</name><name sortKey="Topping, Geoffrey J" sort="Topping, Geoffrey J" uniqKey="Topping G" first="Geoffrey J." last="Topping">Geoffrey J. Topping</name></country><country name="États-Unis"><region name="Wisconsin"><name sortKey="Holden, James E" sort="Holden, James E" uniqKey="Holden J" first="James E." last="Holden">James E. Holden</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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