Simulated apnoeas induce serotonin-dependent respiratory long-term facilitation in rats

Long-term facilitation (LTF) is a form of respiratory neuroplasticity frequently induced by acute intermittent isocapnic hypoxia (AIH, three 5 min isocapnic hypoxic episodes). Although repetitive apnoeas are a frequent natural occurrence producing brief (< 30 s) episodes of hypoxia and hypercapnia, it is unknown if repetitive apnoeas also elicit LTF. Apnoea-induced LTF may preserve upper airway patency during sleep, thereby limiting further apnoeic events. We tested the hypothesis that repeated, brief ventilator-induced apnoeas are sufficient to induce serotonin-dependent phrenic and hypoglossal (XII) LTF in anaesthetized rats. Anaesthetized, male Sprague-Dawley rats were exposed to three or six 25 s ventilator apnoeas with 5 min intervals, and compared to time control and AIH-treated rats. Three and six ventilator apnoeas induced phrenic and XII LTF with a magnitude similar to AIH. Both apnoea-induced and AIH-induced LTF were associated with a decreased CO2 recruitment threshold for phrenic and XII activity (similar to 4 mmHg). Spinal methysergide, a serotonin receptor antagonist, blocked apnoea-induced LTF but not changes in the CO2-recruitment threshold. Thus, brief ventilator apnoeas elicit phrenic and XII LTF. Similar to AIH-induced LTF, apnoea-induced LTF is serotonin dependent, and the relevant serotonin receptors for phrenic LTF are located in the cervical spinal cord. Apnoea-induced LTF may have implications for the maintenance of breathing stability, particularly during sleep.