Pharmacological characterization of serotonergic receptor activity in the hypoglossal nucleus.
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-600175) dose responses were characterized. All drugs were injected unilaterally into the hypoglossal nucleus. The 2A antagonist, MDL-100907, 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-242084, 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-269970, 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.
Fenik
Polina
P
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Veasey
Sigrid C
SC
D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007002:Hypoglossal Nerve / Q000187:drug effects*; D008297:Male; D008845:Microinjections; D009046:Motor Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018490:Serotonin Agents / Q000008:administration & dosage / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D020181:Sleep Apnea, Obstructive / Q000503:physiopathology*
D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D012701:Serotonin; C047087:5-carboxamidotryptamine