Dopamine transporter function assessed by antisense knockdown in the rat: Protection from dopamine neurotoxicity
Identifieur interne : 003513 ( Main/Curation ); précédent : 003512; suivant : 003514Dopamine transporter function assessed by antisense knockdown in the rat: Protection from dopamine neurotoxicity
Auteurs : J. M. Van Kampen [Canada] ; E. G. Mcgeer [Canada] ; A. Jon Stoessl [Canada]Source :
- Synapse [ 0887-4476 ] ; 2000-09-01.
English descriptors
- KwdEn :
- 1-Methyl-4-phenylpyridinium (toxicity), 6‐hydroxydopamine, Amphetamine (pharmacology), Animals, Apomorphine (pharmacology), Autoradiography, Carrier Proteins (genetics), Carrier Proteins (metabolism), Cocaine (analogs & derivatives), Cocaine (metabolism), Corpus Striatum (drug effects), Corpus Striatum (metabolism), Cytoprotection (physiology), Dopamine Plasma Membrane Transport Proteins, Levodopa (pharmacology), MPP+, Male, Membrane Glycoproteins, Membrane Transport Proteins, Microinjections, Motor Activity (drug effects), Nerve Tissue Proteins, Oligonucleotides, Antisense (pharmacology), Oxidopamine (toxicity), RNA, Messenger (antagonists & inhibitors), Rats, Rats, Sprague-Dawley, Substantia Nigra (drug effects), Substantia Nigra (metabolism), Tritium, amphetamine, levodopa, neurotoxicity.
- MESH :
- chemical , analogs & derivatives : Cocaine.
- chemical , antagonists & inhibitors : RNA, Messenger.
- chemical , genetics : Carrier Proteins.
- chemical , metabolism : Carrier Proteins, Cocaine.
- chemical , pharmacology : Amphetamine, Apomorphine, Levodopa, Oligonucleotides, Antisense.
- chemical , toxicity : 1-Methyl-4-phenylpyridinium, Oxidopamine.
- drug effects : Corpus Striatum, Motor Activity, Substantia Nigra.
- metabolism : Corpus Striatum, Substantia Nigra.
- physiology : Cytoprotection.
- Animals, Autoradiography, Dopamine Plasma Membrane Transport Proteins, Male, Membrane Glycoproteins, Membrane Transport Proteins, Microinjections, Nerve Tissue Proteins, Rats, Rats, Sprague-Dawley, Tritium.
Abstract
The plasma membrane dopamine transporter is located on presynaptic nerve terminals and is responsible for the termination of dopaminergic neurotransmission via dopamine reuptake. The dopamine transporter may also contribute to the pathogenesis of Parkinson disease. Dopamine transporter expression correlates well with susceptibility to neuronal degeneration in 1‐methyl‐4‐phenyl‐1,2,3,6 ‐tetrahydropyridine (MPTP)‐induced parkinsonism. Recent studies have implicated the dopamine transporter in the uptake of both this neurotoxin and its metabolite, MPP+, as well as another experimental neurotoxin, 6‐hydroxydopamine. In these studies we examined the role of the dopamine transporter in the neurotoxicity of both MPP+ and 6‐hydroxydopamine in the rat brain using in vivo administration of phosphorothioate antisense oligonucleotides targeting dopamine transporter mRNA. Infusion of dopamine transporter antisense (1 nmol/day, 7 days) into the left substantia nigra pars compacta resulted in reduced 3H‐WIN 35‐428 binding in the left striatum and significant levodopa and amphetamine‐induced contralateral rotations. Unilateral pretreatment with dopamine transporter antisense prior to bilateral intrastriatal infusion of either MPP+ or 6‐hydroxydopamine resulted in asymmetrical striatal 3H‐WIN 35‐428 binding and dopamine content as well as significant apomorphine‐induced ipsilateral rotations, suggesting neuroprotection of nigrostriatal neurons on the antisense‐treated side. Thus, the dopamine transporter appears to play a critical role in determining susceptibility to the experimental neurotoxins MPP+ and 6‐hydroxydopamine. In light of this, the dopamine transporter may prove useful, both as a marker for susceptibility to Parkinson's disease and as a target for therapeutic intervention. Synapse 37:171–178, 2000. © 2000 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/1098-2396(20000901)37:3<171::AID-SYN1>3.0.CO;2-R
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ISTEX:E2DF7878F5224D9B5095653D71FCD06986FB0900Le document en format XML
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Jon Stoessl</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Neurodegenerative Disorders Centre, Faculty of Medicine, University of British Columbia, Vancouver, B.C.</wicri:regionArea><wicri:noRegion>B.C.</wicri:noRegion></affiliation><affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Synapse</title><title level="j" type="abbrev">Synapse</title><idno type="ISSN">0887-4476</idno><idno type="eISSN">1098-2396</idno><imprint><publisher>John Wiley & Sons, Inc.</publisher><pubPlace>New York</pubPlace><date type="published" when="2000-09-01">2000-09-01</date><biblScope unit="volume">37</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="171">171</biblScope><biblScope unit="page" to="178">178</biblScope></imprint><idno type="ISSN">0887-4476</idno></series><idno type="istex">E2DF7878F5224D9B5095653D71FCD06986FB0900</idno><idno type="DOI">10.1002/1098-2396(20000901)37:3<171::AID-SYN1>3.0.CO;2-R</idno><idno type="ArticleID">SYN1</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0887-4476</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenylpyridinium (toxicity)</term><term>6‐hydroxydopamine</term><term>Amphetamine (pharmacology)</term><term>Animals</term><term>Apomorphine (pharmacology)</term><term>Autoradiography</term><term>Carrier Proteins (genetics)</term><term>Carrier Proteins (metabolism)</term><term>Cocaine (analogs & derivatives)</term><term>Cocaine (metabolism)</term><term>Corpus Striatum (drug effects)</term><term>Corpus Striatum (metabolism)</term><term>Cytoprotection (physiology)</term><term>Dopamine Plasma Membrane Transport Proteins</term><term>Levodopa (pharmacology)</term><term>MPP+</term><term>Male</term><term>Membrane Glycoproteins</term><term>Membrane Transport Proteins</term><term>Microinjections</term><term>Motor Activity (drug effects)</term><term>Nerve Tissue Proteins</term><term>Oligonucleotides, Antisense (pharmacology)</term><term>Oxidopamine (toxicity)</term><term>RNA, Messenger (antagonists & inhibitors)</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>Substantia Nigra (drug effects)</term><term>Substantia Nigra (metabolism)</term><term>Tritium</term><term>amphetamine</term><term>levodopa</term><term>neurotoxicity</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Cocaine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>RNA, Messenger</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Carrier Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Carrier Proteins</term><term>Cocaine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Amphetamine</term><term>Apomorphine</term><term>Levodopa</term><term>Oligonucleotides, Antisense</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>1-Methyl-4-phenylpyridinium</term><term>Oxidopamine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Corpus Striatum</term><term>Motor Activity</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Corpus Striatum</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Cytoprotection</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Autoradiography</term><term>Dopamine Plasma Membrane Transport Proteins</term><term>Male</term><term>Membrane Glycoproteins</term><term>Membrane Transport Proteins</term><term>Microinjections</term><term>Nerve Tissue Proteins</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>Tritium</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The plasma membrane dopamine transporter is located on presynaptic nerve terminals and is responsible for the termination of dopaminergic neurotransmission via dopamine reuptake. The dopamine transporter may also contribute to the pathogenesis of Parkinson disease. Dopamine transporter expression correlates well with susceptibility to neuronal degeneration in 1‐methyl‐4‐phenyl‐1,2,3,6 ‐tetrahydropyridine (MPTP)‐induced parkinsonism. Recent studies have implicated the dopamine transporter in the uptake of both this neurotoxin and its metabolite, MPP+, as well as another experimental neurotoxin, 6‐hydroxydopamine. In these studies we examined the role of the dopamine transporter in the neurotoxicity of both MPP+ and 6‐hydroxydopamine in the rat brain using in vivo administration of phosphorothioate antisense oligonucleotides targeting dopamine transporter mRNA. Infusion of dopamine transporter antisense (1 nmol/day, 7 days) into the left substantia nigra pars compacta resulted in reduced 3H‐WIN 35‐428 binding in the left striatum and significant levodopa and amphetamine‐induced contralateral rotations. Unilateral pretreatment with dopamine transporter antisense prior to bilateral intrastriatal infusion of either MPP+ or 6‐hydroxydopamine resulted in asymmetrical striatal 3H‐WIN 35‐428 binding and dopamine content as well as significant apomorphine‐induced ipsilateral rotations, suggesting neuroprotection of nigrostriatal neurons on the antisense‐treated side. Thus, the dopamine transporter appears to play a critical role in determining susceptibility to the experimental neurotoxins MPP+ and 6‐hydroxydopamine. In light of this, the dopamine transporter may prove useful, both as a marker for susceptibility to Parkinson's disease and as a target for therapeutic intervention. Synapse 37:171–178, 2000. © 2000 Wiley‐Liss, Inc.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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