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Long-Term Intermittent Hypoxia

Reduced Excitatory Hypoglossal Nerve Output

Center for Sleep and Respiratory Neurobiology, Division of Sleep Medicine, Department of Medicine, and Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Sigrid Carlen Veasey, M.D., 972 Maloney Bldg., 600 Spruce St., Philadelphia, PA 19104. E-mail: veasey{at}mail.med.upenn.edu

Humans with long-standing sleep apnea show mixed responses to serotonergic therapies for obstructive sleep apnea. We hypothesize that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to 3 weeks of intermittent hypoxia showed reduced hypoglossal nerve responsiveness (logEC₅₀) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to -amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was no reduction in hypoglossal motoneuron soma number or in serotonergic postsynaptic receptor mRNA copy numbers within single-cells; in contrast, there was an increase in isoprostanes in the dorsal medulla. Systemic 4-hydroxyl-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol) throughout exposure to intermittent hypoxia improved the EC₅₀ for serotonin to a larger extent than glutamate and normalized medullary isoprostanes. Protein kinase C activity within the hypoglossal nucleus was increased after long-term intermittent hypoxia. These results suggest that long-term intermittent hypoxia reduces serotonergic and N-methyl-D-aspartate excitatory output of hypoglossal nerves, and that reduced excitatory responsiveness and lipid peroxidation are largely prevented with superoxide dismutase treatment throughout hypoxia/reoxygenation. Similar alterations in neurochemical responsiveness may occur in select persons with obstructive sleep apnea.

Key Words: glutamate • microinjection • serotonin • signal transduction

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