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Pharmacological Characterization of Serotonergic Receptor Activity in the Hypoglossal Nucleus

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

Correspondence and requests for reprints should be addressed to Sigrid Carlen Veasey, M.D., 987 Maloney Building, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104. E-mail: veasey{at}mail.med.upenn.edu

State-dependent reductions in serotonin delivery to upper airway dilator motoneuron activity may contribute to sleep apnea. The functional significance of serotonin receptor subtypes implicated in excitation of dilator motor neurons was evaluated in anesthetized, paralyzed, mechanically ventilated adult rats (n = 108). The effects of antagonists selective for serotonin receptor subtypes 2A, 2C, or 7 on intrinsic hypoglossal activity and on serotonin agonist (serotonin, 5-carboxamidotryptamine maleate, and RO-600,175) dose responses were characterized. All drugs were injected unilaterally into the hypoglossal nucleus. The 2A antagonist, MDL-100,907, dropped intrinsic hypoglossal nerve respiratory activity by 61 ± 6% (p < 0.001) and suppressed serotonin excitation of hypoglossal nerve activity (p < 0.05). The 2C antagonist, SB-242,084, dropped hypoglossal nerve activity 17 ± 6% (p < 0.05) and suppressed the dose–response curve for the 2C agonist. Rapid desensitization occurred with the 2C agonist only (p < 0.05). The 7 antagonist, SB-269,970, had no effect on either intrinsic activity or agonist responses. We conclude that serotonin 2A is the predominant excitatory serotonin receptor subtype at hypoglossal motor neurons. The serotonin 2C excitatory effects are of lower magnitude and are associated with rapid desensitization. There is no evidence for serotonin 7 activity in the hypoglossal nucleus. This characterization of serotonin receptor subtypes in the hypoglossal nucleus provides a focus for the development of pharmacotherapies for sleep apnea.

Key Words: motor neurons • respiratory • serotonin • microinjection • obstructive sleep apnea

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