Endogenous Excitatory Drive Modulating Respiratory Muscle Activity across Sleep–Wake States

Abstract

The concept of a tonic drive activating respiratory muscle in wakefulness but not sleep has been an important and enduring notion in respiratory medicine, not least because it is useful in modeling sleep effects on breathing and understanding the pathogenesis of sleep-related breathing disorders such as obstructive sleep apnea. However, a neurotransmitter substrate mediating respiratory muscle activation across sleep-wake states has not been identified. We determined if alpha1 receptor antagonism at the hypoglossal motor nucleus (HMN) decreases genioglossus (GG) activity consistent with a role for an endogenous noradrenergic drive contributing to GG activation across sleep-wake states. We also determined if alpha1 receptor stimulation could counteract reduced endogenous noradrenergic drive and increase sleeping GG activity. Thirty-five rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states and GG and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN. Microdialysis perfusion of the alpha1 receptor antagonist terazosin into the HMN significantly decreased GG activity in wakefulness and nonrapid eye movement (non-REM) sleep but not REM sleep. The alpha1 receptor agonist phenylephrine increased GG activity in wakefulness and sleep, but periods of motor inactivity persisted in REM sleep; there was no potentiating effect of combined alpha1 and 5-HT2 receptor stimulation. Identification of an endogenous noradrenergic drive contributing to GG activation in wakefulness and non-REM sleep, but not REM sleep, is important given the prevalence and clinical significance of sleep-induced hypoventilation and obstructive sleep apnea in humans and the potential for pharmacologic treatment.