Acute intermittent hypoxia induces phrenic long‐term facilitation which is modulated by 5‐HT_1A receptor in the caudal raphe region of the rat

Abstract

SUMMARYObstructive sleep apnoea (OSA) is characterized by periods of upper airway collapse accompanied by repeated episodes of hypoxia. In experimental animals repeated bouts of hypoxia may evoke sustained augmentation of phrenic nerve activity, known as phrenic long-term facilitation (pLTF). This form of physiological compensation might contribute to stable breathing, minimizing the occurrence of apnoeas and ⁄ or hypopnoeas during sleep in patients with OSA. Serotonin (5-HT) has been shown to modulate respiratory neuronal activity, possibly via projections originating in the raphe nuclei. Our model focuses on the effects of 5-HT 1A receptors blockade by selective antagonist WAY-100635 into the caudal raphe region on phrenic long-term facilitation after exposure to acute intermittent hypoxia (AIH) episodes. Adult, male, urethane-anaesthetized, vagotomized, paralyzed and mechanically ventilated Sprague-Dawley rats were exposed to AIH protocol. Experimental group received microinjection of WAY-100635 into the caudal raphe nucleus, whereas the control group received saline into the same site. Peak phrenic nerve activity and respiratory rhythm parameters were analysed during five hypoxic episodes, as well as at 15, 30 and 60 min after the end of hypoxias. In the control group, 1 h post-hypoxia pLTF was developed. Microinjections of selective 5-HT 1A receptor antagonist WAY-100635 into the raphe nuclei prior to the AIH protocol prevented induction of pLTF. These results suggest that 5-HT 1A receptor activation at supraspinal level is important for induction of pLTF, which is suggested to be an important respiratory neuroplasticity model in animal studies that possibly correlates with OSA in humans.

Sympathetic and Catecholaminergic Alterations in Sleep Apnea with Particular Emphasis on Children

“…In parallel, extensive changes occur in central neural regions governing autonomic system nervous system outflow and other integrated outputs such as respiration (Ai et al, 2009). These changes notwithstanding, a multiplicity of interactions and additional mechanisms are likely involved and are dependent on the age at which IH occurs, the severity, cycle duration, and overall duration of IH, and the association of additional perturbations such as hypercapnia or hypocapnia (Waters and Gozal, 2003; Reeves et al, 2006; Mahamed and Mitchell, 2008; Iturriaga et al, 2009; Zoccal et al, 2009; Kline, 2010; Xing and Pilowsky, 2010; Baker-Herman and Strey, 2011; Dodig et al, 2011; Molkov et al, 2011; Prabha et al, 2011). …”

Generation of active expiration by serotoninergic mechanisms of the ventral medulla of rats

“…By the fact that microinjections of ketanserin in the RTN/pFRG inhibit the effects of IH on abdominal activity, we propose that IH causes a long-lasting activation of the RTN/pFRG expiratory oscillator through a 5-HT 2 -mediated mechanism. The serotoninergic neurons of the caudal raphe (17,51), particularly from raphe magnus and raphe obscurus (46), may be an important source of 5-HT to the RTN/pFRG during IH. This possibility agrees with studies showing that hypoxia activates neurons in the caudal raphe (17,18) and the antagonism of serotoninergic receptors in this region prevents the respiratory changes induced by IH (61).…”

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

“…; Pavlinac Dodig et al . ) depend on activation of 5‐HT receptors, suggesting serotonin‐dependent respiratory motor output facilitation. In addition, both lesion of 5‐HT neurons and systemic injection of 5‐HT receptor antagonists increased the firing activity of noradrenergic neurons (Aghajanian et al .…”

“…; Pavlinac Dodig et al . ) prevented the development of pLTF, allowing development of pLTD in a ‘push–pull’ manner.…”