5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats
Serotonergic (5-HT) receptors are upregulated following spinal cord transection. Stimulation by administration of serotonergic receptor agonists has been successful in improving hindlimb function. We tested whether this strategy would be successful in incomplete injury models (moderate or severe tho...
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| Veröffentlicht in: | Experimental neurology 2010-01, Vol.221 (1), p.68-78 |
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| creator | Hayashi, Y. Jacob-Vadakot, S. Dugan, E.A. McBride, S. Olexa, R. Simansky, K. Murray, M. Shumsky, J.S. |
| description | Serotonergic (5-HT) receptors are upregulated following spinal cord transection. Stimulation by administration of serotonergic receptor agonists has been successful in improving hindlimb function. We tested whether this strategy would be successful in incomplete injury models (moderate or severe thoracic contusion) where descending projections are partially spared which should produce less denervation-induced receptor upregulation. Adult rats received midthoracic moderate (MOD: 25 mm drop) or severe (SEV: 50 mm drop) contusion injuries. Distribution of 5-HT and its transporter and expression of 5-HT
2C receptors were evaluated in lumbar spinal cord and motor response to 5-HT receptor activation was assessed using open field locomotion (BBB) score, percent weight supported treadmill stepping (%WS) and evaluation of hindlimb muscle activation (tremor and serotonin syndrome).
5-HT immunostaining 3 months post-contusion revealed few 5-HT fibers caudal to the severe contusion, and more spared caudal to the moderate contusion. The distribution of 5-HT transporter paralleled 5-HT staining, but was more greatly reduced. Thus serotonin reuptake may be less efficient in the injured spinal cord. Immunostaining for the 5-HT
2C receptor in the dorsal and ventral horns at L5 showed significant upregulation in SEV, compared to sham or MOD rats.
Neither 5-HT
2C nor 5-HT
1A receptor agonists, alone or in combination, nor the serotonin transporter inhibitor
d-fenfluramine modified BBB scores or %WS in either group. Despite the increased sensitivity of post-synaptic targets, agonist treatment did not improve function in SEV rats. We conclude that selective 5-HT
2C or 5-HT
1A receptor activation was not effective in improving hindlimb function after incomplete lesions. In contrast, the 5-HT precursor 5-hydroxytryptophan (
l-5-HTP), which leads to activation of all classes of 5-HT receptors, increased both %WS and hindlimb activity in the MOD group. While no side effects were observed in normal or MOD rats, SEV rats displayed hindlimb tremors and 33% mortality, indicating hypersensitivity to the precursor. |
| doi_str_mv | 10.1016/j.expneurol.2009.10.003 |
| format | Article |
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2C receptors were evaluated in lumbar spinal cord and motor response to 5-HT receptor activation was assessed using open field locomotion (BBB) score, percent weight supported treadmill stepping (%WS) and evaluation of hindlimb muscle activation (tremor and serotonin syndrome).
5-HT immunostaining 3 months post-contusion revealed few 5-HT fibers caudal to the severe contusion, and more spared caudal to the moderate contusion. The distribution of 5-HT transporter paralleled 5-HT staining, but was more greatly reduced. Thus serotonin reuptake may be less efficient in the injured spinal cord. Immunostaining for the 5-HT
2C receptor in the dorsal and ventral horns at L5 showed significant upregulation in SEV, compared to sham or MOD rats.
Neither 5-HT
2C nor 5-HT
1A receptor agonists, alone or in combination, nor the serotonin transporter inhibitor
d-fenfluramine modified BBB scores or %WS in either group. Despite the increased sensitivity of post-synaptic targets, agonist treatment did not improve function in SEV rats. We conclude that selective 5-HT
2C or 5-HT
1A receptor activation was not effective in improving hindlimb function after incomplete lesions. In contrast, the 5-HT precursor 5-hydroxytryptophan (
l-5-HTP), which leads to activation of all classes of 5-HT receptors, increased both %WS and hindlimb activity in the MOD group. While no side effects were observed in normal or MOD rats, SEV rats displayed hindlimb tremors and 33% mortality, indicating hypersensitivity to the precursor.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2009.10.003</identifier><identifier>PMID: 19840787</identifier><identifier>CODEN: EXNEAC</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>5-HT 2C receptor ; 5-HT transporter ; 5-Hydroxytryptophan - therapeutic use ; Animals ; Biological and medical sciences ; Carbidopa - pharmacology ; Carbidopa - therapeutic use ; Cervical Vertebrae - pathology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; DPAT ; Drug Administration Routes ; Drug Administration Schedule ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Exercise Test - methods ; Exploratory Behavior - drug effects ; Female ; Fenfluramine ; Hindlimb - drug effects ; Hindlimb - physiopathology ; Injuries of the nervous system and the skull. Diseases due to physical agents ; l-5-HTP ; Laminectomy - adverse effects ; mCPP ; Medical sciences ; Motor Activity - drug effects ; Movement Disorders - drug therapy ; Movement Disorders - etiology ; Neurology ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT2C - metabolism ; Serotonin - metabolism ; Serotonin 5-HT2 Receptor Agonists ; Serotonin Plasma Membrane Transport Proteins - metabolism ; Serotonin Receptor Agonists - therapeutic use ; Spinal cord contusion ; Spinal Cord Injuries - complications ; Spinal Cord Injuries - metabolism ; Spinal Cord Injuries - pathology ; Stereotyped Behavior - drug effects ; Time Factors ; Traumas. Diseases due to physical agents ; Tremor - drug therapy ; Tremor - etiology ; Up-Regulation - drug effects</subject><ispartof>Experimental neurology, 2010-01, Vol.221 (1), p.68-78</ispartof><rights>2009 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>2009 Elsevier Inc. All rights reserved. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c535t-3c53fa5af53d2527227f2aa861e53ddb148660cbc4969a37a3e3b37691ae85923</citedby><cites>FETCH-LOGICAL-c535t-3c53fa5af53d2527227f2aa861e53ddb148660cbc4969a37a3e3b37691ae85923</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.expneurol.2009.10.003$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22352821$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19840787$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hayashi, Y.</creatorcontrib><creatorcontrib>Jacob-Vadakot, S.</creatorcontrib><creatorcontrib>Dugan, E.A.</creatorcontrib><creatorcontrib>McBride, S.</creatorcontrib><creatorcontrib>Olexa, R.</creatorcontrib><creatorcontrib>Simansky, K.</creatorcontrib><creatorcontrib>Murray, M.</creatorcontrib><creatorcontrib>Shumsky, J.S.</creatorcontrib><title>5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Serotonergic (5-HT) receptors are upregulated following spinal cord transection. Stimulation by administration of serotonergic receptor agonists has been successful in improving hindlimb function. We tested whether this strategy would be successful in incomplete injury models (moderate or severe thoracic contusion) where descending projections are partially spared which should produce less denervation-induced receptor upregulation. Adult rats received midthoracic moderate (MOD: 25 mm drop) or severe (SEV: 50 mm drop) contusion injuries. Distribution of 5-HT and its transporter and expression of 5-HT
2C receptors were evaluated in lumbar spinal cord and motor response to 5-HT receptor activation was assessed using open field locomotion (BBB) score, percent weight supported treadmill stepping (%WS) and evaluation of hindlimb muscle activation (tremor and serotonin syndrome).
5-HT immunostaining 3 months post-contusion revealed few 5-HT fibers caudal to the severe contusion, and more spared caudal to the moderate contusion. The distribution of 5-HT transporter paralleled 5-HT staining, but was more greatly reduced. Thus serotonin reuptake may be less efficient in the injured spinal cord. Immunostaining for the 5-HT
2C receptor in the dorsal and ventral horns at L5 showed significant upregulation in SEV, compared to sham or MOD rats.
Neither 5-HT
2C nor 5-HT
1A receptor agonists, alone or in combination, nor the serotonin transporter inhibitor
d-fenfluramine modified BBB scores or %WS in either group. Despite the increased sensitivity of post-synaptic targets, agonist treatment did not improve function in SEV rats. We conclude that selective 5-HT
2C or 5-HT
1A receptor activation was not effective in improving hindlimb function after incomplete lesions. In contrast, the 5-HT precursor 5-hydroxytryptophan (
l-5-HTP), which leads to activation of all classes of 5-HT receptors, increased both %WS and hindlimb activity in the MOD group. While no side effects were observed in normal or MOD rats, SEV rats displayed hindlimb tremors and 33% mortality, indicating hypersensitivity to the precursor.</description><subject>5-HT 2C receptor</subject><subject>5-HT transporter</subject><subject>5-Hydroxytryptophan - therapeutic use</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Carbidopa - pharmacology</subject><subject>Carbidopa - therapeutic use</subject><subject>Cervical Vertebrae - pathology</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>DPAT</subject><subject>Drug Administration Routes</subject><subject>Drug Administration Schedule</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Exercise Test - methods</subject><subject>Exploratory Behavior - drug effects</subject><subject>Female</subject><subject>Fenfluramine</subject><subject>Hindlimb - drug effects</subject><subject>Hindlimb - physiopathology</subject><subject>Injuries of the nervous system and the skull. Diseases due to physical agents</subject><subject>l-5-HTP</subject><subject>Laminectomy - adverse effects</subject><subject>mCPP</subject><subject>Medical sciences</subject><subject>Motor Activity - drug effects</subject><subject>Movement Disorders - drug therapy</subject><subject>Movement Disorders - etiology</subject><subject>Neurology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor, Serotonin, 5-HT2C - metabolism</subject><subject>Serotonin - metabolism</subject><subject>Serotonin 5-HT2 Receptor Agonists</subject><subject>Serotonin Plasma Membrane Transport Proteins - metabolism</subject><subject>Serotonin Receptor Agonists - therapeutic use</subject><subject>Spinal cord contusion</subject><subject>Spinal Cord Injuries - complications</subject><subject>Spinal Cord Injuries - metabolism</subject><subject>Spinal Cord Injuries - pathology</subject><subject>Stereotyped Behavior - drug effects</subject><subject>Time Factors</subject><subject>Traumas. Diseases due to physical agents</subject><subject>Tremor - drug therapy</subject><subject>Tremor - etiology</subject><subject>Up-Regulation - drug effects</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi0EokvhL4AvcGoWf-TzglRVQJEqcSlna-JMFq-ydvA4FfDrcdjVAicutjTPM-ORX8ZeSbGVQtZv91v8PntcYpi2SoguV7dC6EdsI0UnClVq8ZhthJBlUbZtfcGeEe1FFkvVPGUXsmtL0bTNhv2sitt7Pke0S6QQ-RRgcH53xfslcR8S_80zxjllDLvgHSW64s7biEBI_BBWMi7eJhc8hzFh5DQ7DxO3IQ758GmhlbmMh2VKPEKi5-zJCBPhi9N9yb58eH9_c1vcff746eb6rrCVrlKh8zVCBWOlB1WpRqlmVABtLTFXhl6WbV0L29uyqzvQDWjUvW7qTgK2Vaf0JXt3nDsv_QEHiz5FmMwc3QHiDxPAmX-Jd1_NLjwY1UpVlyIPeHMaEMO3BSmZgyOL0wQew0JGSaXzt3dZbI6ijYEo4nh-RAqz5mb25pybWXNbQc4td778e8c_faegsvD6JABZmMYI3jo6e0rpSrVKZu_66GH-0QeH0ZB16C0OLoeYzBDcf5f5BZP9vXo</recordid><startdate>20100101</startdate><enddate>20100101</enddate><creator>Hayashi, Y.</creator><creator>Jacob-Vadakot, S.</creator><creator>Dugan, E.A.</creator><creator>McBride, S.</creator><creator>Olexa, R.</creator><creator>Simansky, K.</creator><creator>Murray, M.</creator><creator>Shumsky, J.S.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>5PM</scope></search><sort><creationdate>20100101</creationdate><title>5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats</title><author>Hayashi, Y. ; Jacob-Vadakot, S. ; Dugan, E.A. ; McBride, S. ; Olexa, R. ; Simansky, K. ; Murray, M. ; Shumsky, J.S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c535t-3c53fa5af53d2527227f2aa861e53ddb148660cbc4969a37a3e3b37691ae85923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>5-HT 2C receptor</topic><topic>5-HT transporter</topic><topic>5-Hydroxytryptophan - therapeutic use</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Carbidopa - pharmacology</topic><topic>Carbidopa - therapeutic use</topic><topic>Cervical Vertebrae - pathology</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>DPAT</topic><topic>Drug Administration Routes</topic><topic>Drug Administration Schedule</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Exercise Test - methods</topic><topic>Exploratory Behavior - drug effects</topic><topic>Female</topic><topic>Fenfluramine</topic><topic>Hindlimb - drug effects</topic><topic>Hindlimb - physiopathology</topic><topic>Injuries of the nervous system and the skull. Diseases due to physical agents</topic><topic>l-5-HTP</topic><topic>Laminectomy - adverse effects</topic><topic>mCPP</topic><topic>Medical sciences</topic><topic>Motor Activity - drug effects</topic><topic>Movement Disorders - drug therapy</topic><topic>Movement Disorders - etiology</topic><topic>Neurology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor, Serotonin, 5-HT2C - metabolism</topic><topic>Serotonin - metabolism</topic><topic>Serotonin 5-HT2 Receptor Agonists</topic><topic>Serotonin Plasma Membrane Transport Proteins - metabolism</topic><topic>Serotonin Receptor Agonists - therapeutic use</topic><topic>Spinal cord contusion</topic><topic>Spinal Cord Injuries - complications</topic><topic>Spinal Cord Injuries - metabolism</topic><topic>Spinal Cord Injuries - pathology</topic><topic>Stereotyped Behavior - drug effects</topic><topic>Time Factors</topic><topic>Traumas. Diseases due to physical agents</topic><topic>Tremor - drug therapy</topic><topic>Tremor - etiology</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hayashi, Y.</creatorcontrib><creatorcontrib>Jacob-Vadakot, S.</creatorcontrib><creatorcontrib>Dugan, E.A.</creatorcontrib><creatorcontrib>McBride, S.</creatorcontrib><creatorcontrib>Olexa, R.</creatorcontrib><creatorcontrib>Simansky, K.</creatorcontrib><creatorcontrib>Murray, M.</creatorcontrib><creatorcontrib>Shumsky, J.S.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hayashi, Y.</au><au>Jacob-Vadakot, S.</au><au>Dugan, E.A.</au><au>McBride, S.</au><au>Olexa, R.</au><au>Simansky, K.</au><au>Murray, M.</au><au>Shumsky, J.S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2010-01-01</date><risdate>2010</risdate><volume>221</volume><issue>1</issue><spage>68</spage><epage>78</epage><pages>68-78</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><coden>EXNEAC</coden><abstract>Serotonergic (5-HT) receptors are upregulated following spinal cord transection. Stimulation by administration of serotonergic receptor agonists has been successful in improving hindlimb function. We tested whether this strategy would be successful in incomplete injury models (moderate or severe thoracic contusion) where descending projections are partially spared which should produce less denervation-induced receptor upregulation. Adult rats received midthoracic moderate (MOD: 25 mm drop) or severe (SEV: 50 mm drop) contusion injuries. Distribution of 5-HT and its transporter and expression of 5-HT
2C receptors were evaluated in lumbar spinal cord and motor response to 5-HT receptor activation was assessed using open field locomotion (BBB) score, percent weight supported treadmill stepping (%WS) and evaluation of hindlimb muscle activation (tremor and serotonin syndrome).
5-HT immunostaining 3 months post-contusion revealed few 5-HT fibers caudal to the severe contusion, and more spared caudal to the moderate contusion. The distribution of 5-HT transporter paralleled 5-HT staining, but was more greatly reduced. Thus serotonin reuptake may be less efficient in the injured spinal cord. Immunostaining for the 5-HT
2C receptor in the dorsal and ventral horns at L5 showed significant upregulation in SEV, compared to sham or MOD rats.
Neither 5-HT
2C nor 5-HT
1A receptor agonists, alone or in combination, nor the serotonin transporter inhibitor
d-fenfluramine modified BBB scores or %WS in either group. Despite the increased sensitivity of post-synaptic targets, agonist treatment did not improve function in SEV rats. We conclude that selective 5-HT
2C or 5-HT
1A receptor activation was not effective in improving hindlimb function after incomplete lesions. In contrast, the 5-HT precursor 5-hydroxytryptophan (
l-5-HTP), which leads to activation of all classes of 5-HT receptors, increased both %WS and hindlimb activity in the MOD group. While no side effects were observed in normal or MOD rats, SEV rats displayed hindlimb tremors and 33% mortality, indicating hypersensitivity to the precursor.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>19840787</pmid><doi>10.1016/j.expneurol.2009.10.003</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Experimental neurology, 2010-01, Vol.221 (1), p.68-78 |
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| subjects | 5-HT 2C receptor 5-HT transporter 5-Hydroxytryptophan - therapeutic use Animals Biological and medical sciences Carbidopa - pharmacology Carbidopa - therapeutic use Cervical Vertebrae - pathology Disease Models, Animal Dose-Response Relationship, Drug DPAT Drug Administration Routes Drug Administration Schedule Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Exercise Test - methods Exploratory Behavior - drug effects Female Fenfluramine Hindlimb - drug effects Hindlimb - physiopathology Injuries of the nervous system and the skull. Diseases due to physical agents l-5-HTP Laminectomy - adverse effects mCPP Medical sciences Motor Activity - drug effects Movement Disorders - drug therapy Movement Disorders - etiology Neurology Rats Rats, Sprague-Dawley Receptor, Serotonin, 5-HT2C - metabolism Serotonin - metabolism Serotonin 5-HT2 Receptor Agonists Serotonin Plasma Membrane Transport Proteins - metabolism Serotonin Receptor Agonists - therapeutic use Spinal cord contusion Spinal Cord Injuries - complications Spinal Cord Injuries - metabolism Spinal Cord Injuries - pathology Stereotyped Behavior - drug effects Time Factors Traumas. Diseases due to physical agents Tremor - drug therapy Tremor - etiology Up-Regulation - drug effects |
| title | 5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats |
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