Suppression of genioglossus muscle tone and activity during reflex hypercapnic stimulation by GABAa mechanisms at the hypoglossal motor nucleus in vivo

Liu, X.; Sood, Sandeep; Liu, H.; Nolan, P.; Morrison, Janna L.; Horner, Richard L.

doi:10.1016/s0306-4522(02)00564-x

Cited by 32 publications

(39 citation statements)

References 39 publications

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“…The suppressant effects of ethanol on state-dependent arousal processes were also observed in sleep, e.g., as judged by the reduced ratio of high-frequency (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) to low-frequency (0.5-2 Hz) EEG power (i.e., the ␤ 2 -to-␦ 1 ratio) with ethanol in non-REM sleep (Fig. 4).…”

Section: Interpretation Of Findings and Methodological Considerationsmentioning

confidence: 82%

“…Such a range would not have been possible to replicate over the course of an experiment in a conscious rat for any given sleep-wake state, not least because of the added complexity of the spontaneous changes in behavioral state and motor activities that typify the behaving preparation. Also, importantly, if ethanol were exerting its physiological actions to suppress hypoglossal motor output to GG muscle via an effect at the hypoglossal motor pool, then this would also be expected to be documented in the anesthetized preparation, inasmuch as glycine and GABA inhibitory mechanisms are operative under such conditions (29,39).…”

Section: Study 3: Ethanol At the Hypoglossal Motor Pool And Effects Omentioning

confidence: 99%

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

Vecchio

Grace²,

Liu

et al. 2010

Journal of Applied Physiology

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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 ...

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Section: Interpretation Of Findings and Methodological Considerationsmentioning

confidence: 82%

Section: Study 3: Ethanol At the Hypoglossal Motor Pool And Effects Omentioning

confidence: 99%

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

Vecchio

Grace²,

Liu

et al. 2010

Journal of Applied Physiology

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“…We microdialyzed 1 mM glycine and 1 M muscimol (GABA A receptor agonist) into the left trigeminal motor pool before and while simultaneously applying 0.1 mM strychnine and 0.1 mM bicuculline. We used these doses of glycine and GABA A receptor agonists because they suppress genioglossus muscle EMG activity when applied to the hypoglossal motor pool in anesthetized rats (Morrison et al, 2002;Liu et al, 2003). All manipulations were made during waking when masseter muscle tone was maximal so the inhibitory effects of glycine and muscimol would induce the greatest degree of suppression.…”

Section: Study 4: Is Rem Atonia Mediated By Increased Inhibition and mentioning

confidence: 99%

Glycinergic and GABA_A-Mediated Inhibition of Somatic Motoneurons Does Not Mediate Rapid Eye Movement Sleep Motor Atonia

Brooks¹,

Peever²

2008

J. Neurosci.

118

106

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A hallmark of rapid eye movement (REM) sleep is a potent suppression of postural muscle tone. Motor control in REM sleep is unique because it is characterized by flurries of intermittent muscle twitches that punctuate muscle atonia. Because somatic motoneurons are bombarded by strychnine-sensitive IPSPs during REM sleep, it is assumed that glycinergic inhibition underlies REM atonia. However, it has never been determined whether glycinergic inhibition of motoneurons is indeed responsible for triggering the loss of postural muscle tone during REM sleep. Therefore, we used reverse microdialysis, electrophysiology, and pharmacological and histological methods to determine whether glycinergic and/or GABA A -mediated neurotransmission at the trigeminal motor pool mediates masseter muscle atonia during REM sleep in rats. By antagonizing glycine and GABA A receptors on trigeminal motoneurons, we unmasked a tonic glycinergic/GABAergic drive at the trigeminal motor pool during waking and non-rapid eye movement (NREM) sleep. Blockade of this drive potently increased masseter muscle tone during both waking and NREM sleep. This glycinergic/GABAergic drive was immediately switched-off and converted into a phasic glycinergic drive during REM sleep. Blockade of this phasic drive potently provoked muscle twitch activity in REM sleep; however, it did not prevent or reverse REM atonia. Muscle atonia in REM even persisted when glycine and GABA A receptors were simultaneously antagonized and trigeminal motoneurons were directly activated by glutamatergic excitation, indicating that a powerful, yet unidentified, inhibitory mechanism overrides motoneuron excitation during REM sleep. Our data refute the prevailing hypothesis that REM atonia is caused by glycinergic inhibition. The inhibitory mechanism mediating REM atonia therefore requires reevaluation.

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“…For example, GABAergic mechanisms may modulate mXII activity during respiration via ventral RF pathways (Donato and Nistri, 2000;Liu et al, 2003) and GABAergic neurons projecting to mXII from MdD and MdV could also be involved in lingual reflexes evoked by nociceptive input (Villanueva et al, 1996;Monconduit et al, 2002).…”

Section: Neurotransmitter Phenotypes Of Preoromotor Neuronsmentioning

confidence: 99%

Neurotransmitter phenotypes of intermediate zone reticular formation projections to the motor trigeminal and hypoglossal nuclei in the rat

Travers

Yoo

Chandran

et al. 2005

J of Comparative Neurology

100

105

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Numerous studies suggest an essential role for the intermediate (IRt) and parvocellular (PCRt) reticular formation (RF) in consummatory ingestive responses. Although the IRt and PCRt contain a large proportion of neurons with projections to the oromotor nuclei, these areas of the RF are heterogeneous with respect to neurotransmitter phenotypes. Glutamatergic, GABAergic, cholinergic, and nitrergic neurons are all found in the PCRt and IRt, but the projections of neurons with these phenotypes to the motor trigeminal (mV) and hypoglossal nucleus (mXII) has not been fully evaluated. In the present study, after small injections of Fluorogold (FG) into mV and mXII, sections were processed immunohistochemically to detect retrogradely labeled FG neurons in combination with the synthetic enzymes for nitric oxide (nitric oxide synthase) or acetylcholine (choline acetyltransferase) or in situ hybridization for the synthetic enzyme for GABA (GAD65/67) or the brainstem vesicular transporter for glutamate (VGLUT2). In three additional cases, FG injections were made into one motor nucleus and cholera toxin (subunit b) injected in the other to determine the presence of dual projection neurons. Premotor neurons to mXII (pre-mXII) were highly concentrated in the IRt. In contrast, there were nearly equal proportions of premotor-trigeminal neurons (pre-mV) in the IRt and PCRt. A high proportion of pre-oromotor neurons were positive for VGLUT2 (pre-mXII: 68%; pre-mV: 53%) but GABAergic projections were differentially distributed with a greater projection to mV (25%) compared to mXII (8%). Significant populations of cholinergic and nitrergic neurons overlapped pre-oromotor neurons, but there was sparse double-labeling (<10%). The IRt also contained a high proportion of neurons that projected to both mV and MXII. These different classes of premotor neurons in the IRt and PCRt provide a substrate for the rhythmic activation of lingual and masticatory muscles.

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Suppression of genioglossus muscle tone and activity during reflex hypercapnic stimulation by GABAa mechanisms at the hypoglossal motor nucleus in vivo

Cited by 32 publications

References 39 publications

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

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

Glycinergic and GABA_A-Mediated Inhibition of Somatic Motoneurons Does Not Mediate Rapid Eye Movement Sleep Motor Atonia

Neurotransmitter phenotypes of intermediate zone reticular formation projections to the motor trigeminal and hypoglossal nuclei in the rat

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Suppression of genioglossus muscle tone and activity during reflex hypercapnic stimulation by GABAa mechanisms at the hypoglossal motor nucleus in vivo

Cited by 32 publications

References 39 publications

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

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

Glycinergic and GABAA-Mediated Inhibition of Somatic Motoneurons Does Not Mediate Rapid Eye Movement Sleep Motor Atonia

Neurotransmitter phenotypes of intermediate zone reticular formation projections to the motor trigeminal and hypoglossal nuclei in the rat

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Glycinergic and GABA_A-Mediated Inhibition of Somatic Motoneurons Does Not Mediate Rapid Eye Movement Sleep Motor Atonia