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Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats

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Side 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. Bishop

Source :

British Journal of Pharmacology [ 0007-1188 ] ; 2014.

RBID : PMC:4280972

Abstract

BACKGROUND AND PURPOSE

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-HT₁_A 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.

EXPERIMENTAL APPROACH

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-HT₁_A agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT₁_A 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.

KEY RESULTS

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.

CONCLUSIONS AND IMPLICATIONS

The results suggest that compounds that indirectly facilitate 5-HT₁_A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT₁_A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280972

DOI: 10.1111/bph.12894
PubMed: 25175895
PubMed Central: 4280972

Affiliations:

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PMC:4280972

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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>
</author>
<author><name sortKey="Vilceus, N" sort="Vilceus, N" uniqKey="Vilceus N" first="N" last="Vilceus">N. Vilceus</name>
</author>
<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>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">Br J Pharmacol</journal-id>
<journal-id journal-id-type="iso-abbrev">Br. J. Pharmacol</journal-id>
<journal-id journal-id-type="publisher-id">bph</journal-id>
<journal-title-group><journal-title>British Journal of Pharmacology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0007-1188</issn>
<issn pub-type="epub">1476-5381</issn>
<publisher><publisher-name>Blackwell Publishing Ltd</publisher-name>
<publisher-loc>Oxford, UK</publisher-loc>
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<article-meta><article-id pub-id-type="pmid">25175895</article-id>
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<article-id pub-id-type="doi">10.1111/bph.12894</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Papers</subject>
</subj-group>
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<title-group><article-title>Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Lindenbach</surname>
<given-names>D</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Palumbo</surname>
<given-names>N</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Ostock</surname>
<given-names>C Y</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Vilceus</surname>
<given-names>N</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Conti</surname>
<given-names>M M</given-names>
</name>
</contrib>
<contrib contrib-type="author"><name><surname>Bishop</surname>
<given-names>C</given-names>
</name>
</contrib>
<aff><institution>Behavioral Neuroscience Program, Department of Psychology, Binghamton University – State University of New York</institution>
<addr-line>Binghamton, NY, USA</addr-line>
</aff>
</contrib-group>
<author-notes><corresp id="cor1">Dr Christopher Bishop, Psychology Department, Binghamton University, PO Box 6000, Binghamton, NY 13901-6000, USA. E-mail: <email>cbishop@binghamton.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>1</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub"><day>24</day>
<month>11</month>
<year>2014</year>
</pub-date>
<volume>172</volume>
<issue>1</issue>
<fpage>119</fpage>
<lpage>130</lpage>
<history><date date-type="received"><day>12</day>
<month>5</month>
<year>2014</year>
</date>
<date date-type="rev-recd"><day>18</day>
<month>7</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>26</day>
<month>8</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 The British Pharmacological Society</copyright-statement>
<copyright-year>2014</copyright-year>
</permissions>
<abstract><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>
</abstract>
</article-meta>
</front>
</pmc>
<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>
</noCountry>
</tree>
</affiliations>
</record>

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Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats

Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats

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Abstract

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