Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats
Identifieur interne : 000058 ( Main/Exploration ); précédent : 000057; suivant : 000059Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats
Auteurs : D. Lindenbach ; N. Palumbo ; C Ostock ; N. Vilceus ; M Conti ; C. BishopSource :
- British Journal of Pharmacology [ 0007-1188 ] ; 2014.
Abstract
Treatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT1A receptor, but these drugs have been reported to worsen PD features and are known to produce ‘5-HT syndrome’, symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia.
Sprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT1A agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT1A agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia.
Each 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome.
The results suggest that compounds that indirectly facilitate 5-HT1A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT1A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile.
Url:
DOI: 10.1111/bph.12894
PubMed: 25175895
PubMed Central: 4280972
Affiliations:
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Le document en format XML
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<author><name sortKey="Lindenbach, D" sort="Lindenbach, D" uniqKey="Lindenbach D" first="D" last="Lindenbach">D. Lindenbach</name>
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<author><name sortKey="Palumbo, N" sort="Palumbo, N" uniqKey="Palumbo N" first="N" last="Palumbo">N. Palumbo</name>
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<author><name sortKey="Ostock, C Y" sort="Ostock, C Y" uniqKey="Ostock C" first="C" last="Ostock">C Ostock</name>
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<author><name sortKey="Vilceus, N" sort="Vilceus, N" uniqKey="Vilceus N" first="N" last="Vilceus">N. Vilceus</name>
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<author><name sortKey="Conti, M M" sort="Conti, M M" uniqKey="Conti M" first="M" last="Conti">M Conti</name>
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<author><name sortKey="Bishop, C" sort="Bishop, C" uniqKey="Bishop C" first="C" last="Bishop">C. Bishop</name>
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<author><name sortKey="Palumbo, N" sort="Palumbo, N" uniqKey="Palumbo N" first="N" last="Palumbo">N. Palumbo</name>
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<author><name sortKey="Ostock, C Y" sort="Ostock, C Y" uniqKey="Ostock C" first="C" last="Ostock">C Ostock</name>
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<author><name sortKey="Vilceus, N" sort="Vilceus, N" uniqKey="Vilceus N" first="N" last="Vilceus">N. Vilceus</name>
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<author><name sortKey="Conti, M M" sort="Conti, M M" uniqKey="Conti M" first="M" last="Conti">M Conti</name>
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<author><name sortKey="Bishop, C" sort="Bishop, C" uniqKey="Bishop C" first="C" last="Bishop">C. Bishop</name>
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<series><title level="j">British Journal of Pharmacology</title>
<idno type="ISSN">0007-1188</idno>
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<front><div type="abstract" xml:lang="en"><sec><title>BACKGROUND AND PURPOSE</title>
<p>Treatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT<sub>1</sub>
<sub>A</sub>
receptor, but these drugs have been reported to worsen PD features and are known to produce ‘5-HT syndrome’, symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia.</p>
</sec>
<sec><title>EXPERIMENTAL APPROACH</title>
<p>Sprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT<sub>1</sub>
<sub>A</sub>
agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT<sub>1</sub>
<sub>A</sub>
agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia.</p>
</sec>
<sec><title>KEY RESULTS</title>
<p>Each 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome.</p>
</sec>
<sec><title>CONCLUSIONS AND IMPLICATIONS</title>
<p>The results suggest that compounds that indirectly facilitate 5-HT<sub>1</sub>
<sub>A</sub>
receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT<sub>1</sub>
<sub>A</sub>
receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile.</p>
</sec>
</div>
</front>
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<affiliations><list></list>
<tree><noCountry><name sortKey="Bishop, C" sort="Bishop, C" uniqKey="Bishop C" first="C" last="Bishop">C. Bishop</name>
<name sortKey="Conti, M M" sort="Conti, M M" uniqKey="Conti M" first="M" last="Conti">M Conti</name>
<name sortKey="Lindenbach, D" sort="Lindenbach, D" uniqKey="Lindenbach D" first="D" last="Lindenbach">D. Lindenbach</name>
<name sortKey="Ostock, C Y" sort="Ostock, C Y" uniqKey="Ostock C" first="C" last="Ostock">C Ostock</name>
<name sortKey="Palumbo, N" sort="Palumbo, N" uniqKey="Palumbo N" first="N" last="Palumbo">N. Palumbo</name>
<name sortKey="Vilceus, N" sort="Vilceus, N" uniqKey="Vilceus N" first="N" last="Vilceus">N. Vilceus</name>
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