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5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats. 2010

Y Hayashi, and S Jacob-Vadakot, and E A Dugan, and S McBride, and R Olexa, and K Simansky, and M Murray, and J S Shumsky
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.

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.

UI MeSH Term Description Entries
D007796 Laminectomy A surgical procedure that entails removing all (laminectomy) or part (laminotomy) of selected vertebral lamina to relieve pressure on the SPINAL CORD and/or SPINAL NERVE ROOTS. Vertebral lamina is the thin flattened posterior wall of vertebral arch that forms the vertebral foramen through which pass the spinal cord and nerve roots. Laminotomy,Laminectomies,Laminotomies
D009043 Motor Activity Body movements of a human or an animal as a behavioral phenomenon. Activities, Motor,Activity, Motor,Motor Activities
D009069 Movement Disorders Syndromes which feature DYSKINESIAS as a cardinal manifestation of the disease process. Included in this category are degenerative, hereditary, post-infectious, medication-induced, post-inflammatory, and post-traumatic conditions. Dyskinesia Syndromes,Etat Marbre,Status Marmoratus,Movement Disorder Syndromes,Dyskinesia Syndrome,Movement Disorder,Movement Disorder Syndrome
D002230 Carbidopa An inhibitor of DOPA DECARBOXYLASE that prevents conversion of LEVODOPA to dopamine. It is used in PARKINSON DISEASE to reduce peripheral adverse effects of LEVODOPA. It has no anti-parkinson activity by itself. Methyldopahydrazine,Carbidopa, (R)-Isomer,Carbidopa, (S)-Isomer,Lodosin,Lodosyn,MK-485,MK-486,MK 485,MK 486,MK485,MK486
D002574 Cervical Vertebrae The first seven VERTEBRAE of the SPINAL COLUMN, which correspond to the VERTEBRAE of the NECK. Cervical Spine,Cervical Spines,Spine, Cervical,Vertebrae, Cervical
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004333 Drug Administration Routes The various ways of administering a drug or other chemical to a site in a patient or animal from where the chemical is absorbed into the blood and delivered to the target tissue. Administration Routes, Drug,Administration Route, Drug,Drug Administration Route,Route, Drug Administration,Routes, Drug Administration
D004334 Drug Administration Schedule Time schedule for administration of a drug in order to achieve optimum effectiveness and convenience. Administration Schedule, Drug,Administration Schedules, Drug,Drug Administration Schedules,Schedule, Drug Administration,Schedules, Drug Administration
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme

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