State-dependent vs. central motor effects of ethanol on breathing

Abstract

Ethanol, one of the most widely used drugs in Western society, worsens obstructive sleep apnea in humans. No studies, however, have distinguished between two primary mechanisms that could mediate suppression of genioglossus (GG) activity with ethanol. We test the hypothesis that ethanol suppresses GG activity by effects at the hypoglossal motor pool and/or by state-dependent regulation of motor activity via independent influences on sleep/arousal processes. Intraperitoneal injections of ethanol (1.25 g/kg, n ϭ 6 rats) resulted in maximum blood levels of 125.5 Ϯ 15.8 mg/dl, i.e., physiologically relevant levels for producing behavioral impairment in rats and humans. Ethanol decreased wakefulness, reduced sleep latency, and increased non-rapid eye movement sleep (P Ͻ 0.001, n ϭ 10 rats) and significantly reduced postural muscle tone and electroencephalogram frequencies, consistent with sedation. Ethanol also caused a state-dependent (wakefulness only) decrease in respiratory-related GG activity (P ϭ 0.018) but did not affect diaphragm amplitude or rate, with the magnitude of GG decrease related to baseline activity (P Ͻ 0.0002). Ethanol did not alter GG activity when applied to the hypoglossal motor pool (0.025-1 M, n ϭ 16 isoflurane-anesthetized rats). In conclusion, ethanol promoted sleep and altered electroencephalogram and postural motor activities, indicative of sedation. The lack of effect on GG with ethanol at the hypoglossal motor pool indicates that the GG and postural motor suppression following systemic administration was mediated via effects on state-dependent/arousal-related processes. These data show that ethanol can suppress GG by primary influences on state-dependent aspects of central nervous system function independent of effects on the respiratory network per se, a distinction that has not previously been identified experimentally.sleep; genioglossus muscle; obstructive sleep apnea OBSTRUCTIVE SLEEP APNEA-HYPOPNEA (OSAH) constitutes a common respiratory problem and significant public health burden (45,64). Ethanol is one of the most widely used drugs in Western society (61), and one consequence of ethanol ingestion in humans is impairment of breathing during sleep in otherwise-normal individuals and significant worsening of breathing during sleep in individuals with OSAH (2,8,23,36,48,51,52,59). In these clinical studies, ethanol typically increased the frequency and duration of disordered breathing events (2,23,36,48,51). One study in awake humans (27) and another in decerebrate and awake cats (3) reported suppression of genioglossus (GG) activity after ethanol, which may relate to the aforementioned worsening of OSAH (2,23,36,48,51). Importantly, however, no studies have distinguished between the two primary mechanisms that could mediate ethanol-induced suppression of GG activity: 1) a primary state-dependent influence on motor activity via an effect of ethanol on sleep/ arousal processes per se and 2) a motor suppression effect operating via an inhibitory influence of ethanol directly at the ...

Neural Control of the Upper Airway: Integrative Physiological Mechanisms and Relevance for Sleep Disordered Breathing

“…In addition to producing these markers of sleep-promotion/reduced arousal, ethanol also caused a state-dependent decrease in GG activity, but did not affect diaphragm activity or respiratory rate across any sleep-wake state (Fig. 12) (582). The pattern of this state-dependent decrease in GG activity after ethanol was also similar to that produced in the nonrespiratory, postural (neck) muscle by ethanol (Fig.…”

“…Importantly, despite these state-dependent effects of ethanol on GG motor activity following systemic administration, local application of ethanol directly to the hypoglossal motor pool caused no change in GG activity compared to the time-control (sham) experiments with delivery of vehicle control (582). Overall, therefore, these data show that ethanol at physiologically relevant concentrations promotes sleep and alters electroencephalogram and postural motor activities indicative of a sedating effect.…”

“…The evidence that the magnitude of decrease in respiratory-related and tonic GG activities produced by ethanol was related to baseline activity without ethanol ( Fig. 12) (582), that is, the ethanol-induced decrease in activity was larger when baseline activity was higher, has important clinical relevance. The implication of this observation is that individuals with high baseline levels of GG activity, such as OSAH patients who are thought to require this activity to keep to keep the upper airspace open and maintain adequate airflow (306), would be most susceptible to suppression of activity with ethanol, so explaining the worsening of sleep disordered in such individuals (49,104,238,347,473,489,490,542).…”

“…Nevertheless, in vitro studies using neonatal and juvenile rodent brainstem slice preparations have shown that ethanol potentiates inhibitory GABA and glycine receptor function at hypoglossal motoneurons, and augments inhibitory postsynaptic currents (126,127,492). Accordingly, such in vitro studies suggest that, at least in part, some component of the suppression of GG motor tone after ethanol may be due to augmentation of inhibitory neurotransmission at the hypoglossal motor pool, but comparable studies had not been performed in vivo until recently (582). The results of the latter study are discussed below in the context of determining whether ethanol suppresses respiratory muscle activity by effects at the central motor pool and/or by state-dependent regulation of motor activity via influences on sleep/arousal processes.…”

The influence of alcohol on genioglossus single motor units in men and women during wakefulness

“…Data from the placebo session in these participants have been reported in a recent publication (Avraam et al, 2021) (Nicholas et al, 2010;Vecchio et al, 2010;Wilkinson et al, 2008Wilkinson et al, , 2010Woods et al, 2015). Transition of units between IP and IT units is common (Nicholas et al, 2010;Wilkinson et al, 2010), and likewise conversion of EP/ET to TT and vice versa have been observed (Nicholas et al, 2010).…”