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

Abstract

The dorsomedial medulla oblongata (DMM) includes the solitary tract nucleus and the hypoglossal nucleus, to which 5-HT neurons project. Effects of 5-HT in the DMM on ventilatory augmentation and airway dilation are mediated via 5-HT2 receptors, which interact with the CO(2) drive. The interaction may elicit cycles between hyperventilation with airway dilation and hypoventilation with airway narrowing. In the present study, effects of 5-HT2 receptors in the DMM on hypoxic ventilatory and airway responses were investigated, while 5-HT release in the DMM was monitored. Adult male mice were anesthetized, and then a microdialysis probe was inserted into the DMM. The mice were placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to hypoxic gas (7% O(2) in N(2)) for 5 min with or without a 5-HT2 receptor antagonist (LY-53857) perfused in the DMM. 5-HT release in the DMM was increased by hypoxia regardless of the presence of LY-53857. Immediate onset and the peak of initial hypoxic hyperventilatory responses were delayed. Subsequent ventilatory decline and airway dilation during initial hypoxic hyperventilation were suppressed with LY-53857. These results suggest that 5-HT release increased by hypoxia acts on 5-HT2 receptors in the DMM, which contributes to the immediate onset of initial hypoxic hyperventilation, airway dilation, and subsequent ventilatory decline. Hypoxic ventilatory and airway responses mediated via 5-HT2 receptors in the DMM may play roles in immediate rescue and defensive adaptation for hypoxia and may be included in periodic breathing and the pathogenesis of obstructive sleep apnea.

Serotonergic system in hypoxic ventilatory response in unilateral rat model of Parkinson’s disease

“…Some studies pointed that caudal medullary raphe and its serotoninergic neurons are not involved in mediating respiratory response to hypoxia [30] and that absence of serotonin in brains of genetically modified mice has no impact on magnitude of ventilatory long term facilitation following intermittent hypoxia [31]. On the other hand, serotonin released in the area of the dorsomedial medulla oblongata containing NTS and nucleus of hypoglossal nerve participated in initiation of hypoxic ventilatory response and its depressive phase [18]. Antagonism of 5-HT 2 receptors in this localization produced delayed post-hypoxic hyperventilation and reduced depression phase [18].…”

“…On the other hand, serotonin released in the area of the dorsomedial medulla oblongata containing NTS and nucleus of hypoglossal nerve participated in initiation of hypoxic ventilatory response and its depressive phase [18]. Antagonism of 5-HT 2 receptors in this localization produced delayed post-hypoxic hyperventilation and reduced depression phase [18]. …”

“…Moreover, stimulatory 5HT 2 receptors in dorsomedial medulla oblongata have been considered to be responsible for initiation of hypoxic hyperventilation [18]. Chemical lesion of the raphe magnus, where serotonergic neurons are present, produced increased ventilatory response to hypoxia in awake rats [19].…”

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

“…Excitatory drive to the caudal NTS, which relays airway irritation into coughing and sneezing depends on NMDA and non-NMDA receptor input (478). Kanamaru showed that 5-HT2 receptors were involved in transmission of the acute hypoxic signal in the medial NTS (316). In anesthetized rats, vagal inhibition of NTS neurons is mediated by GABA-A and GABA-B receptors (737).…”

Activation of 5-hyrdoxytryptamine 7 receptors within the rat nucleus tractus solitarii modulates synaptic properties

“…For instance, 5-HT 1A Rs are located postsynaptically on nTS neurons where they inhibit evoked and spontaneous excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) and decrease respiration (Ostrowski et al, 2014). Activation of 5-HT 2 R in the nTS lowers heart rate, blood pressure, and delays the hypoxic ventilatory response (Comet et al, 2007; Kanamaru and Homma, 2009), and activation of 5-HT 2A R and 5-HT 2C R augment nTS EPSCs (Austgen and Kline, 2013; Austgen et al, 2012). Presynaptic 5-HT 3 Rs augment nTS neurotransmission by increasing spontaneous glutamate release (Cui et al, 2012) as well as inhibit cardiac reflex responses (Sévoz et al, 1997; Weissheimer and Machado, 2007).…”