Compensatory airway dilation and additive ventilatory augmentation mediated by dorsomedial medullary 5-hydroxytryptamine 2 receptor activity and hypercapnia

Abstract

5-HT2 receptor activity in the hypoglossal nucleus and hypercapnia is associated with airway dilation. 5-HT neurons in the medullary raphe and hypercapnia are responsible for tidal volume change. In this study, the effects of 5-HT2 receptors in the dorsomedial medulla oblongata (DMM), which receives projections from the medullary raphe, and hypercapnia on airway resistance and respiratory variables were studied in mice while monitoring 5-HT release in the DMM. A microdialysis probe was inserted into the DMM of anesthetized adult mice. Each mouse was placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to stepwise increases in CO(2) inhalation (5%, 7%, and 9% CO(2) in O(2)) at 8-min intervals with a selective serotonin reuptake inhibitor, fluoxetine, or fluoxetine plus a 5-HT2 receptor antagonist, LY-53857 in the DMM. In response to fluoxetine plus LY-53857 coperfusion, specific airway resistance was increased, and tidal volume and minute ventilation were decreased. CO(2) inhalation with fluoxetine plus LY-53857 coperfusion in the DMM largely decreased airway resistance and additively increased minute ventilation. Thus, 5-HT2 receptor activity in the DMM increases basal levels of airway dilation and ventilatory volume, dependent on central inspiratory activity and the volume threshold of the inspiratory off-switch mechanism. Hypercapnia with low 5-HT2 receptor activity in the DMM largely recovers airway dilation and additively increases ventilatory volume. Interaction between 5-HT2 receptor activity in the DMM and CO(2) drive may elicit a cycle of hyperventilation with airway dilation and hypoventilation with airway narrowing.

Serotonergic mechanisms on breathing modulation in the rat locus coeruleus

“…As a consequence, neuronal firing rate and therefore NA release in LC projection sites would be decreased, reducing the ventilatory response to 7% CO 2 . Corroborating our data, Kanamaru and Homma [32] demonstrated that blockade of 5-HT 2 receptors in the dorsomedial medulla oblongata facilitates ventilation under CO 2 inhalation due to compensatory airway dilation and additive augmentation of ventilatory volume. In the present study, the effect of both Ketanserin and DOI on ventilation was only observed with the higher doses (Figs.…”

Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons

“…There is strong evidence that 5-HT neurons are respiratory CO 2 chemoreceptors, including increased firing rate of 5-HT neurons and 5-HT release during hypercapnia (Veasey et al, 1995;Richerson, 2004;Kanamaru and Homma, 2007). However, the relative contribution of 5-HT neurons to the HCVR compared with other putative chemoreceptors (Mulkey et al, 2004;Putnam et al, 2004) remains unclear (Guyenet et al, 2005;Richerson et al, 2005).…”

“…5-HT neurons respond to hypercapnic acidosis with an increase in activity in vitro (Richerson, 1995;Wang et al, 2001), and in vivo (Larnicol et al, 1994;Veasey et al, 1995;Haxhiu et al, 2001;Johnson et al, 2005), and this causes an increase in 5-HT release in vivo (Kanamaru and Homma, 2007), indicating that 5-HT neurons are modulated by the acid/base status of the brain. There is also evidence for a trophic role for 5-HT, especially during development and after CNS injury (Golder and Mitchell, 2005), as well as a permissive effect for some forms of plasticity such as long-term facilitation of respiratory motor output (Baker-Herman et al, 2004).…”

Dorsomedial medullary 5-HT2 receptors mediate immediate onset of initial hyperventilation, airway dilation, and ventilatory decline during hypoxia in mice

“…Adult male C57BL/6N mice (CLEA Japan, Tokyo, Japan) [12 Ϯ 0.6 wk of age, 25.1 Ϯ 0.6 g (mean Ϯ SE)] were housed on a 12:12-h light-dark cycle with lights on at 8:00 AM and had free access to food and water. The procedure for surgical implantation of the microdialysis probe in the DMM has been described in detail previously (14). Briefly, each mouse was anesthetized with pentobarbital sodium (0.5 mg ⅐ 0.1 ml saline Ϫ1 ⅐ 10 g body wt Ϫ1 ip).…”

“…We have demonstrated that interplay between 5-HT2 receptor activity in the DMM and respiratory CO 2 drive elicits hyperventilation with airway dilation or hypoventilation with airway narrowing (14). The tongue protrudor (genioglossus) and retractor (hyoglossus) muscles are stimulated by hypoxia (8).…”