Eupnea and gasping in vivo are facilitated by the activation of 5-HT2A receptors

Abstract

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_2A) to facilitate eupnea and gasping, here the hypothesis addressed is that 5-HT_2A 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_2A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.p.), a 5-HT_1A 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_2A 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/V̇o₂ compared with TPH2^+/+. As previously reported, the gasping of TPH2^-/- was significantly delayed (P < 0.001) and occurred at a significantly lower frequency compared with TPH2^+/+ (P = 0.04). For both genotypes, DOI hastened eupneic frequency but had no effect on V̇e or V̇e/V̇o₂. 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 (P = 0.01), a delay in the appearance of gasping (P = 0.005), and reduced gasp frequency (P = 0.05). These data show that, in vivo, 5-HT_2A receptors facilitate both eupnea and gasping. As has been shown in vitro, 5-HT_2A probably promotes gasping by exciting hypoxia-resistant pacemaker neurons.NEW & NOTEWORTHY Previous in vitro studies suggest that 5-HT_2A 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_2A receptor activation. Following 5-HT_2A 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_2A receptors.

Keywords: 5-HT2 receptors; eupnea; gasping; respiratory rhythm; serotonin.