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The Journal of Neuroscience, May 15, 2003, 23(10):4182-4189

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Serotonin 1A Receptor Agonists Reverse Respiratory Abnormalities in Spinal Cord-Injured Rats

Yang Dong Teng,¹ Marian Bingaman,¹ Angelo M. Taveira-DaSilva,² Peter P. Pace,² Richard A. Gillis,¹ and Jean R. Wrathall³

Departments of ¹Pharmacology, ²Medicine, and ³Neuroscience, Georgetown University Medical Center, Washington, DC 20057

Contusion spinal cord injury (SCI) at T8 produces respiratory abnormalities in conscious rats breathing room air and challenged with CO₂. In seeking ways to improve respiration after SCI, we tested drugs that stimulate serotonin 1A (5-HT_1A) receptors, based on our previous findings that these agents can counteract respiratory depression produced by morphine overdose. Respiratory function was measured with a head-out plethysmograph system in conscious rats. T8 SCI rats (n = 5) showed decreased tidal volume (Vt; 0.90 ± 0.02-0.66 ± 0.03 ml; p < 0.05) and increased respiratory rate (f;91 ± 3.7-132 ± 5.7 breaths/min; p < 0.05) with room air ventilation at 24 hr after injury. They also exhibited a diminished response to the respiratory stimulating effect of 7% CO₂; minute ventilation increased to 250 ± 17 ml/min before, but only to 162 ± 15 ml/min at 24 hr after SCI (p < 0.05). Respiratory deficits during room air ventilation were also observed at 7 d after injury (n = 3). Treatment with the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH-DPAT; 250µg/kg, i.p.) at 24 hr (n = 5) or 7 d (n = 3) after injury normalized Vt, f, and the respiratory response to 7% CO₂. Identical results were obtained with another 5-HT_1A receptor agonist, buspirone (1.5 mg/kg, i.p.; n = 3). In contrast, intraperitoneal saline vehicle administration (n = 5) showed no beneficial effects on SCI-impaired respiration. Finally, pretreatment with a specific antagonist of 5-HT_1A receptors, 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.; n = 3) given 20 min before 8-OH-DPAT, prevented 8-OH-DPAT from restoring respiration to normal. Our results demonstrate that drugs that stimulate 5-HT_1A receptors counteract respiratory abnormalities in conscious rats after SCI.

Key words: rat; 5-HT1A; 8-OH-DPAT; buspirone; p-MPPI; tidal volume; respiratory rate; minute ventilation; plethysmograph; spinal cord injury

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Received Nov. 18, 2002; revised Feb. 28, 2003; accepted Mar. 5, 2003.

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