title: GABAA receptor antagonism at the hypoglossal motor nucleus increases genioglossus muscle activity in NREM but not REM sleep.
abstract: The pharyngeal muscles, such as the genioglossus (GG) muscle of the tongue, are important for effective lung ventilation since they maintain an open airspace. Rapid-eye-movement (REM) sleep, however, recruits powerful neural mechanisms that can abolish GG activity, even during strong reflex respiratory stimulation by elevated CO2. In vitro studies have demonstrated the presence of GABAA receptors on hypoglossal motoneurons, and these and other data have led to the speculation that GABAA mechanisms may contribute to the suppression of hypoglossal motor outflow to the GG muscle in REM sleep. We have developed an animal model that allows us to chronically manipulate neurotransmission at the hypoglossal motor nucleus using microdialysis across natural sleep-wake states in rats. The present study tests the hypothesis that microdialysis perfusion of the GABAA receptor antagonist bicuculline into the hypoglossal motor nucleus will prevent the suppression of GG muscle activity in REM sleep during both room-air and CO2-stimulated breathing. Ten rats were implanted with electroencephalogram and neck muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes for respiratory muscle recording. Microdialysis probes were implanted into the hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid (ACSF) or 100 microM bicuculline during room-air and CO2-stimulated breathing (7 % inspired CO2). GABAA receptor antagonism at the hypoglossal motor nucleus increased respiratory-related GG activity during both room-air (P = 0.01) and CO2-stimulated breathing (P = 0.007), indicating a background inhibitory GABA tone. However, the effects of bicuculline on GG activity depended on the prevailing sleep-wake state (P < 0.005), with bicuculline increasing GG activity in non-REM (NREM) sleep and wakefulness both in room air and hypercapnia (P < 0.01), but GG activity was effectively abolished in those REM periods without phasic twitches in the GG muscle. This abolition of GG activity in REM sleep occurred regardless of ACSF or bicuculline at the hypoglossal motor nucleus, or room-air or CO2-stimulated breathing (P > 0.63). We conclude that these data in freely behaving rats confirm previous in vitro studies that GABAA receptor mechanisms are present at the hypoglossal motor nucleus and are tonically active, but the data also show that GABAA receptor antagonism at the hypoglossal motor nucleus does not increase GG muscle activity in natural REM sleep.
authors.affiliation: Department of Medicine, University of Toronto, Canada M5S 1A8.
authors.forename: Janna L
authors.initials: JL
authors.lastname: Morrison
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sood
authors.forename: Hattie
authors.initials: H
authors.lastname: Liu
authors.forename: Eileen
authors.initials: E
authors.lastname: Park
authors.forename: Philip
authors.initials: P
authors.lastname: Nolan
authors.forename: Richard L
authors.initials: RL
authors.lastname: Horner
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002245:Carbon Dioxide / Q000494:pharmacology; D004566:Electrodes; D004569:Electroencephalography; D004576:Electromyography; D005452:Fluoresceins; D005456:Fluorescent Dyes; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D007002:Hypoglossal Nerve / Q000187:drug effects*; D008297:Male; D017551:Microdialysis; D010609:Pharyngeal Muscles / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D012890:Sleep / Q000502:physiology*; D012895:Sleep, REM / Q000502:physiology*; D013238:Stereotaxic Techniques; D013268:Stimulation, Chemical
chemical_list: D005452:Fluoresceins; D005456:Fluorescent Dyes; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D002245:Carbon Dioxide; D012701:Serotonin; D001640:Bicuculline