Respiratory abnormalities resulting from midcervical spinal cord injury and their reversal by serotonin 1A agonists in conscious rats

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-HT1A receptors on post-C5 SCI respiratory dysfunction. Treatment with the 5-HT1A agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH DPAT) (250 mu g/kg, i.p.) restored hypercapnic Ve at 2 and 4 weeks after injury (i.e., similar to 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 similar to 4 h (p <= 0.038 and p <= 0.024, respectively). Treatment with another 5-HT1A receptor agonist, buspirone (1.5 mg/kg, i.p.), replicated the results, whereas pretreatment with a 5-HT1A-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-HT1A agonists for post-SCI respiratory disorders.