To improve the pharmacological characterization of the receptors mediating 5-hydroxytryptamine (5-HT)-induced apnea the inhibitory effects of exogenous 5-HT on respiration and phrenic nerve activity (PNA) were studied in anesthetized rats. The effects of putative 5-HT receptor agonists and antagonists on respiratory parameters were examined. During spontaneous respiration the bolus i.v. injection of 5-HT (3.125-25 micrograms/kg) produced a transient apnea, the duration of which increased in a dose-related manner. In addition, during artificial respiration 5-HT produced a silent response of PNA, the duration of which increased dose-dependently. These responses were significantly antagonized by GR38032F, a selective 5-HT3 receptor antagonist. Ketanserin (100 micrograms/kg) and methysergide (100 micrograms/kg), 5-HT2 receptor antagonists, also inhibited the 5-HT-induced apnea. These effects of 5-HT on respiration were mimicked by 2-methyl-5-HT (3.125-25 micrograms/kg), a selective 5-HT3 receptor agonist, and by a high dose of alpha-methyl-5-HT, a 5-HT2 receptor agonist, but not by 5-carboxamidotryptamine, a 5-HT1-like receptor agonist. Lung compliance was greatly reduced and lung resistance greatly increased by 5-HT (3.125-25 micrograms/kg). The 5-HT-induced changes in lung compliance and lung resistance were antagonized markedly by both ketanserin (100 micrograms/kg) and methysergide (100 micrograms/kg), but not by GR38032F (100 micrograms/kg). Bilateral vagotomy above the nodose ganglia completely prevented both the changes in PNA and the apnea induced by 5-HT. These actions of 5-HT were not prevented, however, by cervical vagotomy below the level of the nodose ganglion. On the other hand, this cervical vagotomy completely blocked the alpha-methyl-5-HT-induced apnea.(ABSTRACT TRUNCATED AT 250 WORDS)