Ventilatory mechanical analysis of respiratory depression induced by serotonin

: This study was aimed to prove the pharmacological characteristics of 5-hydroxytryptamine (5-HT)-induced respiratory depression, especially apnea. Effects of 5-HT-receptor agonists and antagonists on respiratory parameters were examined using anesthetized and spontaneously breathing rats. A bolus intravenous administration of 5-HT (3.125-25 micrograms/kg) immediately produced an apnea, the duration of which increased in a dose-related manner. This response was antagonized by a selective 5-HT3-receptor antagonist, GR38032F (10 and 100 micrograms/kg). Ketanserin, a 5-HT2-receptor antagonist, 100 micrograms/kg also inhibited the 5-HT-induced apnea. In addition, the effect of 5-HT-induced apnea mimicked by 2-methyl-5-HT (3.125-50 micrograms/kg), a 5-HT3-receptor agonist, and by alpha-methyl-5-HT (3.125-25 micrograms/kg), a 5-HT2-receptor agonist. On the other hand, 5-HT produced a decrease in lung compliance and an increase in lung resistance in a dose-related manner. The 5-HT-induced changes in lung compliance and lung resistance were antagonized by ketanserin (100 micrograms/kg), but not by GR38032F (100 micrograms/kg). Furthermore, alpha-methyl-5-HT caused bronchoconstriction as did 5-HT, but 2-methyl-5-HT did not. Although bilateral vagotomy at the supra-nodose ganglia completely prevented 5-HT-induced apnea, cervical vagotomy below the superior laryngeal nerve did not prevent this change. On the other hand, cervical vagotomy almost prevented bronchoconstrictive responses, and completely blocked alpha-methyl-5-HT-induced apnea. These results suggest that 5-HT-induced apnea might be mediated through 5-HT3-receptor mechanisms of the vagal afferent system including the nodose ganglia, and that 5-HT2-receptor mechanisms also contribute to the apnea via the afferent cervical vagus nerves. Direct and indirect bronchoconstriction might also be partly involved in 5-HT-induced apnea.