Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson's: an in vivo imaging study.
Identifieur interne : 001E55 ( Main/Exploration ); précédent : 001E54; suivant : 001E56Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson's: an in vivo imaging study.
Auteurs : Vesna Sossi [Canada] ; Katherine Dinelle ; Geoffrey J. Topping ; James E. Holden ; Doris Doudet ; Michael Schulzer ; Thomas J. Ruth ; A Jon Stoessl ; Raul De La Fuente-FernandezSource :
- Journal of neurochemistry [ 1471-4159 ] ; 2009.
English descriptors
- KwdEn :
- Animals, Disease Models, Animal, Dopamine Plasma Membrane Transport Proteins (metabolism), Levodopa (metabolism), Male, Parkinson Disease (diagnostic imaging), Parkinson Disease (metabolism), Positron-Emission Tomography (methods), Protein Binding (physiology), Rats, Rats, Sprague-Dawley, Synapses (diagnostic imaging), Synapses (metabolism).
- MESH :
- chemical , metabolism : Dopamine Plasma Membrane Transport Proteins, Levodopa.
- diagnostic imaging : Parkinson Disease, Synapses.
- metabolism : Parkinson Disease, Synapses.
- methods : Positron-Emission Tomography.
- physiology : Protein Binding.
- Animals, Disease Models, Animal, Male, Rats, Rats, Sprague-Dawley.
Abstract
Studies showed that the dopamine (DA) transporter (DAT) modulates changes in levodopa-derived synaptic dopamine levels (Delta(DA)) in Parkinson's disease (PD). Here we evaluate the relationship between DAT and Delta(DA) in the 6-hydroxydopamine model of Parkinson's disease to investigate these mechanisms as a function of dopaminergic denervation and in relation to other denervation-induced regulatory changes. 27 rats with a unilateral 6-hydroxydopamine lesion (denervation approximately 20-97%) were imaged with (11)C-dihydrotetrabenazine (VMAT2 marker), (11)C-methylphenidate (DAT marker) and (11)C-raclopride (D2-type receptor marker). For denervation <75%Delta(DA) was significantly correlated with a combination of relatively preserved terminal density and lower DAT. For denervation <90%, Delta(DA) was significantly negatively correlated with DAT with a weaker dependence on VMAT2. For the entire data set, no dependence on pre-synaptic markers was observed; Delta(DA) was significantly positively correlated with (11)C-raclopride binding-derived estimates of DA loss. These findings parallel observations in humans, and show that (i) regulatory changes attempt to normalize synaptic DA levels (ii) a lesion-induced functional dependence of Delta(DA) on DAT occurs up to approximately 90% denervation (iii) for denervation < 75% relative lower DAT levels may relate to effective compensation; for higher denervation, lower DAT levels likely contribute to oscillations in synaptic DA associated with dyskinesias.
DOI: 10.1111/j.1471-4159.2009.05904.x
PubMed: 19183257
Affiliations:
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Topping</name></author><author><name sortKey="Holden, James E" sort="Holden, James E" uniqKey="Holden J" first="James E" last="Holden">James E. Holden</name></author><author><name sortKey="Doudet, Doris" sort="Doudet, Doris" uniqKey="Doudet D" first="Doris" last="Doudet">Doris Doudet</name></author><author><name sortKey="Schulzer, Michael" sort="Schulzer, Michael" uniqKey="Schulzer M" first="Michael" last="Schulzer">Michael Schulzer</name></author><author><name sortKey="Ruth, Thomas J" sort="Ruth, Thomas J" uniqKey="Ruth T" first="Thomas J" last="Ruth">Thomas J. Ruth</name></author><author><name sortKey="Stoessl, A Jon" sort="Stoessl, A Jon" uniqKey="Stoessl A" first="A Jon" last="Stoessl">A Jon Stoessl</name></author><author><name sortKey="De La Fuente Fernandez, Raul" sort="De La Fuente Fernandez, Raul" uniqKey="De La Fuente Fernandez R" first="Raul" last="De La Fuente-Fernandez">Raul De La Fuente-Fernandez</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2009">2009</date><idno type="RBID">pubmed:19183257</idno><idno type="pmid">19183257</idno><idno type="doi">10.1111/j.1471-4159.2009.05904.x</idno><idno type="wicri:Area/PubMed/Corpus">000E86</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000E86</idno><idno type="wicri:Area/PubMed/Curation">000E86</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000E86</idno><idno type="wicri:Area/PubMed/Checkpoint">000E86</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000E86</idno><idno type="wicri:Area/Ncbi/Merge">000A24</idno><idno type="wicri:Area/Ncbi/Curation">000A24</idno><idno type="wicri:Area/Ncbi/Checkpoint">000A24</idno><idno type="wicri:Area/Main/Merge">002008</idno><idno type="wicri:Area/Main/Curation">001E55</idno><idno type="wicri:Area/Main/Exploration">001E55</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson's: an in vivo imaging study.</title><author><name sortKey="Sossi, Vesna" sort="Sossi, Vesna" uniqKey="Sossi V" first="Vesna" last="Sossi">Vesna Sossi</name><affiliation wicri:level="1"><nlm:affiliation>Pacific Parkinson's Research Centre, Wesbrook Mall, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Pacific Parkinson's Research Centre, Wesbrook Mall, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Dinelle, Katherine" sort="Dinelle, Katherine" uniqKey="Dinelle K" first="Katherine" last="Dinelle">Katherine Dinelle</name></author><author><name sortKey="Topping, Geoffrey J" sort="Topping, Geoffrey J" uniqKey="Topping G" first="Geoffrey J" last="Topping">Geoffrey J. Topping</name></author><author><name sortKey="Holden, James E" sort="Holden, James E" uniqKey="Holden J" first="James E" last="Holden">James E. Holden</name></author><author><name sortKey="Doudet, Doris" sort="Doudet, Doris" uniqKey="Doudet D" first="Doris" last="Doudet">Doris Doudet</name></author><author><name sortKey="Schulzer, Michael" sort="Schulzer, Michael" uniqKey="Schulzer M" first="Michael" last="Schulzer">Michael Schulzer</name></author><author><name sortKey="Ruth, Thomas J" sort="Ruth, Thomas J" uniqKey="Ruth T" first="Thomas J" last="Ruth">Thomas J. Ruth</name></author><author><name sortKey="Stoessl, A Jon" sort="Stoessl, A Jon" uniqKey="Stoessl A" first="A Jon" last="Stoessl">A Jon Stoessl</name></author><author><name sortKey="De La Fuente Fernandez, Raul" sort="De La Fuente Fernandez, Raul" uniqKey="De La Fuente Fernandez R" first="Raul" last="De La Fuente-Fernandez">Raul De La Fuente-Fernandez</name></author></analytic><series><title level="j">Journal of neurochemistry</title><idno type="eISSN">1471-4159</idno><imprint><date when="2009" type="published">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Dopamine Plasma Membrane Transport Proteins (metabolism)</term><term>Levodopa (metabolism)</term><term>Male</term><term>Parkinson Disease (diagnostic imaging)</term><term>Parkinson Disease (metabolism)</term><term>Positron-Emission Tomography (methods)</term><term>Protein Binding (physiology)</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>Synapses (diagnostic imaging)</term><term>Synapses (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine Plasma Membrane Transport Proteins</term><term>Levodopa</term></keywords><keywords scheme="MESH" qualifier="diagnostic imaging" xml:lang="en"><term>Parkinson Disease</term><term>Synapses</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Parkinson Disease</term><term>Synapses</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Positron-Emission Tomography</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Protein Binding</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Male</term><term>Rats</term><term>Rats, Sprague-Dawley</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Studies showed that the dopamine (DA) transporter (DAT) modulates changes in levodopa-derived synaptic dopamine levels (Delta(DA)) in Parkinson's disease (PD). Here we evaluate the relationship between DAT and Delta(DA) in the 6-hydroxydopamine model of Parkinson's disease to investigate these mechanisms as a function of dopaminergic denervation and in relation to other denervation-induced regulatory changes. 27 rats with a unilateral 6-hydroxydopamine lesion (denervation approximately 20-97%) were imaged with (11)C-dihydrotetrabenazine (VMAT2 marker), (11)C-methylphenidate (DAT marker) and (11)C-raclopride (D2-type receptor marker). For denervation <75%Delta(DA) was significantly correlated with a combination of relatively preserved terminal density and lower DAT. For denervation <90%, Delta(DA) was significantly negatively correlated with DAT with a weaker dependence on VMAT2. For the entire data set, no dependence on pre-synaptic markers was observed; Delta(DA) was significantly positively correlated with (11)C-raclopride binding-derived estimates of DA loss. These findings parallel observations in humans, and show that (i) regulatory changes attempt to normalize synaptic DA levels (ii) a lesion-induced functional dependence of Delta(DA) on DAT occurs up to approximately 90% denervation (iii) for denervation < 75% relative lower DAT levels may relate to effective compensation; for higher denervation, lower DAT levels likely contribute to oscillations in synaptic DA associated with dyskinesias.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="De La Fuente Fernandez, Raul" sort="De La Fuente Fernandez, Raul" uniqKey="De La Fuente Fernandez R" first="Raul" last="De La Fuente-Fernandez">Raul De La Fuente-Fernandez</name><name sortKey="Dinelle, Katherine" sort="Dinelle, Katherine" uniqKey="Dinelle K" first="Katherine" last="Dinelle">Katherine Dinelle</name><name sortKey="Doudet, Doris" sort="Doudet, Doris" uniqKey="Doudet D" first="Doris" last="Doudet">Doris Doudet</name><name sortKey="Holden, James E" sort="Holden, James E" uniqKey="Holden J" first="James E" last="Holden">James E. Holden</name><name sortKey="Ruth, Thomas J" sort="Ruth, Thomas J" uniqKey="Ruth T" first="Thomas J" last="Ruth">Thomas J. Ruth</name><name sortKey="Schulzer, Michael" sort="Schulzer, Michael" uniqKey="Schulzer M" first="Michael" last="Schulzer">Michael Schulzer</name><name sortKey="Stoessl, A Jon" sort="Stoessl, A Jon" uniqKey="Stoessl A" first="A Jon" last="Stoessl">A Jon Stoessl</name><name sortKey="Topping, Geoffrey J" sort="Topping, Geoffrey J" uniqKey="Topping G" first="Geoffrey J" last="Topping">Geoffrey J. Topping</name></noCountry><country name="Canada"><noRegion><name sortKey="Sossi, Vesna" sort="Sossi, Vesna" uniqKey="Sossi V" first="Vesna" last="Sossi">Vesna Sossi</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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