Eupnea and Gasping in Vivo Are Facilitated by the Activation of 5-HT Receptors

Eupnea and gasping in infancy depend on central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT). Although previous in vitro preparations have provided some evidence that 5-HT acts through type 2 A receptors (5-HT) to facilitate eupnea and gasping, here the hypothesis addressed is that 5-HT receptor activation is necessary for eupnea and the proper generation of gasping in vivo. To test this, we administered 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25 mg/kg i.p.), a 5-HT agonist, 8-hydroxy-2-(di--propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.p.), a 5-HT agonist, or vehicle (saline) to 7-9-day-old tryptophan hydroxylase 2 knockout (TPH2) mice. A second experiment assessed the effect of MDL-11,939 (MDL; 10 mg/kg i.p.), the specific 5-HT antagonist, or vehicle (DMSO) on the gasping of wild-type (TPH2) animals. Drugs were given 15 min prior to five episodes of severe hypoxia that elicited gasping. TPH2 breathed more slowly but had the same V̇e and V̇e/V̇o compared with TPH2. As previously reported, the gasping of TPH2 was significantly delayed ( < 0.001) and occurred at a significantly lower frequency compared with TPH2 ( = 0.04). For both genotypes, DOI hastened eupneic frequency but had no effect on V̇e or V̇e/V̇o. The gasping of TPH2, although unaffected by 8-OH-DPAT, was indistinguishable from the gasping of TPH2 following DOI. In TPH2, application of MDL led to hypoventilation ( = 0.01), a delay in the appearance of gasping ( = 0.005), and reduced gasp frequency ( = 0.05). These data show that, in vivo, 5-HT receptors facilitate both eupnea and gasping. As has been shown in vitro, 5-HT probably promotes gasping by exciting hypoxia-resistant pacemaker neurons. Previous in vitro studies suggest that 5-HT receptors contribute to eupnea and are necessary for fictive gasping. The current study shows that the impaired gasping displayed by neonatal TPH2 mice, deficient in CNS serotonin, is restored by 5-HT receptor activation. Following 5-HT blockade, wild-type mice hypoventilated and their gasping resembled that of TPH2 mice. This study shows that both eupnea and gasping in vivo rely on the activation of 5-HT receptors.