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The Journal of Neuroscience, May 4, 2005, 25(18):4550-4559; doi:10.1523/JNEUROSCI.5135-04.2005

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Development/Plasticity/Repair
Respiratory Abnormalities Resulting from Midcervical Spinal Cord Injury and their Reversal by Serotonin 1A Agonists in Conscious Rats

Howard Choi,^1,2,3 Wei-Lee Liao,^1,2,3 Kimberly M. Newton,^1,3 Renna C. Onario,^1,3 Allyson M. King,^1,3 Federico C. Desilets,^1,3 Eric J. Woodard,¹ Marc E. Eichler,¹ Walter R. Frontera,² Sunil Sabharwal,^2,3 and Yang D. Teng^1,2,3

¹Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital and Children's Hospital Boston, Boston, Massachusetts 02115, ²Department of Physical Medicine and Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, Massachusetts 02114, and ³Spinal Cord Injury Research and Service, Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts 02132

Respiratory dysfunction after cervical spinal cord injury (SCI) has not been examined experimentally using conscious animals, although clinical SCI most frequently occurs in midcervical segments. Here, we report a C5 hemicontusion SCI model in rats with abnormalities that emulate human post-SCI pathophysiology, including spontaneous recovery processes. Post-C5 SCI rats demonstrated deficits in minute ventilation (Ve) responses to a 7% CO₂ challenge that correlated significantly with lesion severities (no injury or 12.5, 25, or 50 mm x 10 g weight drop; New York University impactor; p < 0.001) and ipsilateral motor neuron loss (p = 0.016). Importantly, C5 SCI resulted in at least 4 weeks of respiratory abnormalities that ultimately recovered afterward. Because serotonin is involved in respiration-related neuroplasticity, we investigated the impact of activating 5-HT_1A receptors on post-C5 SCI respiratory dysfunction. Treatment with the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH DPAT) (250 µg/kg, i.p.) restored hypercapnic Ve at 2 and 4 weeks after injury (i.e., 39.2% increase vs post-SCI baseline; p 0.033). Improvements in hypercapnic Ve response after single administration of 8-OH DPAT were dose dependent and lasted for 4 h(p 0.038 and p 0.024, respectively). Treatment with another 5-HT_1A receptor agonist, buspirone (1.5 mg/kg, i.p.), replicated the results, whereas pretreatment with a 5-HT_1A-specific antagonist, 4-iodo-N-[2-[4(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.) given 20 min before 8-OH DPAT negated the effect of 8-OH DPAT. These results imply a potential clinical use of 5-HT_1A agonists for post-SCI respiratory disorders.

Key words: spinal cord injury; cervical; hemicontusion; respiration; serotonin 1A; buspirone

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Received Sep 28, 2004; revised March 28, 2005; accepted March 30, 2005.

This article has been cited by other articles:

				M. Yamauchi, J. Dostal, H. Kimura, and K. P. Strohl Effects of buspirone on posthypoxic ventilatory behavior in the C57BL/6J and A/J mouse strains J Appl Physiol, August 1, 2008; 105(2): 518 - 526. [Abstract] [Full Text] [PDF]

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