Apnea‐induced respiratory long‐term facilitation of genioglossus motor outflow requires noradrenergic receptor activation on hypoglossal motoneurons

Abstract

The respiratory neuronal network is highly flexible and can undergo neuroplasticity, one form of which is called long-term facilitation (LTF). Current data suggests that concurrent episodic activation of serotonin 2A (5-HT2A) and α1 noradrenergic receptors underlie hypoxia-induced LTF of breathing. The aims of this study were to determine: 1) whether apnea-induced LTF of genioglossus (GG) muscle tone involves 5-HT2A and/or α1-dependent processes, and 2) if the underlying mechanisms are operating at the level of hypoglossal motoneurons. LTF was measured as a along-lasting (> 1-hour) enhancement in inspiratory GG EMG activity following repeated apneas in spontaneously breathing, anesthetized adult rats. We found that systemic administration (i.v.) of either the α1 receptor antagonist terazosin (15ug/kg; n=5), or the 5-HT2A receptor antagonist ketanserin (2 mg/kg; n=6) prevented apnea-induced LTF (p=0.343 and p=0.073 respectively). Expression of apnea-induced LTF was dependent on the activation of α1 receptors on hypoglossal motoneurons because microdialysis of terazosin (1 uM; n=6) into the hypoglossal motor pool abolished LTF (p=0.10), whereas ketanserin perfusion did not (50 uM, n=6; p= 0.001 and 100 uM, n=4; p=0.006). Our data indicates that repeated apneas result in activation of α1-dependent processes within hypoglossal motoneurons, leading to enhancement of upper airway activity. 5-HT2A receptor activation may in turn be required elsewhere in the respiratory network, upstream of motoneurons. Grant Funding Source: NSERC