Intermittent hypercapnia‐induced phrenic long‐term depression is revealed after serotonin receptor blockade with methysergide in anaesthetized rats

Abstract

New Findings r What is the central question of this study?Intermittent hypercapnia is a concomitant feature of breathing disorders. Hypercapnic stimuli evoke a form of respiratory plasticity known as phrenic long-term depression in experimental animals. This study was performed to investigate the putative role of serotonin receptors in the initiation of phrenic long-term depression in anaesthetized rats. r What is the main finding and its importance?Phrenic nerve long-term depression was revealed in animals pretreated with the serotonin broad-spectrum antagonist, methysergide. This study highlights that serotonin receptors modulate respiratory plasticity evoked by acute intermittent hypercapnia in anaesthetized rats.This study was performed to test the hypothesis that intermittent hypercapnia can evoke a form of respiratory plasticity known as long-term depression of the phrenic nerve (pLTD) and that 5-HT receptors play a role in the initiation of pLTD. Adult male urethane-anaesthetized, vagotomized, paralysed, mechanically ventilated Sprague-Dawley rats were exposed to an acute intermittent hypercapnia protocol. One group received i.v. injection of the non-selective 5-HT receptor antagonist methysergide and another group received i.v. injection of the selective 5-HT 1A receptor antagonist WAY-100635 20 min before exposure to intermittent hypercapnia. A control group received i.v. injection of saline. Peak phrenic nerve activity and respiratory rhythm parameters were analysed at baseline (T0), during each of five hypercapnic episodes, and 15, 30 and 60 min (T60) after the last hypercapnia. Intravenous injection of methysergide before exposure to acute intermittent hypercapnia induced development of amplitude pLTD at T60 (decreased by 46.1 ± 6.9%, P = 0.003). Conversely, in control and WAY-100635-pretreated animals, exposure to acute intermittent hypercapnia did not evoke amplitude pLTD. However, a long-term decrease in phrenic nerve frequency was evoked both in control (42 ± 4 breaths min −1 at T0 versus 32 ± 5 breaths min −1 at T60; P = 0.036) and in methysergide-pretreated animals (42 ± 2 breaths min −1 at T0 versus 32 ± 3 breaths min −1 at T60; P = 0.028). In WAY-100635 pretreated animals, frequency pLTD was prevented. These results suggest that 5-HT receptors modulate respiratory plasticity induced by acute intermittent hypercapnia in anaesthetized rats.

Blast from the past! Phrenic motor memory of antecedent episodic hypercapnia is serotonin dependent: relevance to respiratory rehabilitation and sleep‐disordered breathing?

“…The study by Valic et al . () extends our appreciation of the manifestations and mechanisms of respiratory plasticity and further implicates aminergic‐dependent signalling as the basis for persistent motor memory in efferent pathways controlling lung ventilation after exposure to episodic blood gas disturbance.…”

“…Serotonin receptors are further implicated in respiratory LTD given the observation in the study by Valic et al . () that respiratory frequency LTD was not apparent in animals pretreated systemically with WAY‐100635, a 5‐HT 1A receptor antagonist.…”

“…In this issue of Experimental Physiology , Valic et al . () explore the oft‐overlooked stimulus of intermittent hypercapnia, a feature of disordered breathing that results from recurrent pauses in respiration, termed apnoeas. Whether a failing of the brainstem network (central) or a consequence of periodic occlusions of the pharyngeal airway (obstructive), recurrent apnoeas can give rise to exposure to intermittent hypercapnia, which in turn can elicit a long‐lasting inhibition of respiratory motor activity, so‐called long‐term depression (LTD).…”

“…In a rat model, Valic et al . () demonstrate that five bouts of hypercapnia, interspersed with equivalent durations of normocapnia, result in a persistent memory of the antecedent episodic hypercapnia through a form of respiratory LTD that features a slowing of respiratory frequency (Bach & Mitchell, ), notwithstanding the apparent restoration of ‘baseline’ conditions, readily achievable by use of an anaesthetized, mechanically ventilated experimental preparation. Systemic administration of the broad‐spectrum serotonergic antagonist methysergide before exposure to episodic hypercapnia revealed an additional component of respiratory LTD manifest in the major efferent motor pathway of breathing, i.e.…”

Plasticity in respiratory motor neurons in response to reduced synaptic inputs: A form of homeostatic plasticity in respiratory control?

“…However, compensatory changes in respiratory motor neurons may occur following more long-lasting increases in respiratory neural activity. Of note, prolonged or intermittent exposures to elevated levels of CO 2 elicit a rebound depression in phrenic burst amplitude (Baker et al, 2001, Valic et al, 2016), although the mechanisms underlying this depression are incompletely understood.…”