Application of histamine or serotonin to the hypoglossal nucleus increases genioglossus muscle activity across the wake–sleep cycle

Abstract

SUMMAR Y The decrease in genioglossus (GG) muscle activity during sleep, especially rapid eye movement (REM) or paradoxical sleep, can lead to airway occlusion and obstructive sleep apnoea (OSA). The hypoglossal nucleus innervating the GG muscle is under the control of serotonergic, noradrenergic and histaminergic neurons that cease firing during paradoxical sleep. The objectives of this study were to determine the effect on GG muscle activity during different wake-sleep states of the microdialysis application of serotonin, histamine (HA) or noradrenaline (NE) to the hypoglossal nucleus in freely moving cats. Six adult cats were implanted with electroencephalogram, electrooculogram and neck electromyogram electrodes to record wake-sleep states and with GG muscle and diaphragm electrodes to record respiratory muscle activity. Microdialysis probes were inserted into the hypoglossal nucleus for monoamine application. Changes in GG muscle activity were assessed by power spectrum analysis. In the baseline conditions, tonic GG muscle activity decreased progressively and significantly from wakefulness to slow-wave sleep and even further during slow-wave sleep with ponto-geniculo-occipital waves and paradoxical sleep. Application of serotonin or HA significantly increased GG muscle activity during the wake-sleep states when compared with controls. By contrast, NE had no excitatory effect. Our results indicate that both serotonin and HA have a potent excitatory action on GG muscle activity, suggesting multiple aminergic control of upper airway muscle activity during the wake-sleep cycle. These data might help in the development of pharmacological approaches for the treatment of OSA.k e y w o r d s genioglossus, histamine, hypoglossus, noradrenaline, obstructive sleep apnoea, serotonin, sleep INTRODUCTIONThe activity of the genioglossus (GG) muscle, innervated by the hypoglossal (XII) motor nucleus (HMN), contributes to the maintenance of upper airway patency (Ryan and Bradley, 2005;White, 2006). During sleep, especially rapid eye movement (REM) or paradoxical sleep (PS), GG muscle activity decreases in animals (Horner et al., 2002;Megirian et al., 1985) and humans (Katz and White, 2004;Sauerland and Harper, 1976). In individuals with an anatomically small pharyngeal airway, this decrease in GG muscle activity can lead to airway occlusion (Remmers et al., 1978), i.e. obstructive sleep apnoea (OSA), a sleep disorder affecting up to 4% of adults (Young et al., 1993). The mechanisms responsible for this selective obstruction of the upper airway during PS remain unclear and pharmacological therapies have not Correspondence: Pierre-Charles Neuzeret, INSERM U628, Physiologie Inte´gre´e du Syste`me dÕEveil,

Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus

“…Data from healthy animals show that sleep-related withdrawal of aminergic (NE and 5-HT) activation is a major mechanism responsible for sleep-related depression of upper airway muscle activity (9,(11)(12)(13)20). This wake-related aminergic drive is derived from NE and 5-HT cells of the brainstem (14)(15)(16).…”

“…When NE or 5-HT are applied onto XII motoneurons in vivo, their dominant effect is excitation mediated by a 1 -adrenergic and 5-HT 2 receptors, respectively (9)(10)(11)(12)(13)20). These effects are exerted postsynaptically on the corresponding receptors expressed in XII motoneurons (21, 23, 33, 51, 52).…”

“…This drive is derived from pontomedullary NE and 5-HT cells (14)(15)(16) that have state-dependent levels of activity, maximal during wakefulness, moderate during non-REM sleep, and minimal or absent during REM sleep (17)(18)(19). The sleep-related withdrawal of aminergic (NE and 5-HT) activation has been identified as a major mechanism underlying sleep-related depression of upper airway muscle activity (9,12,13,20). The excitatory effects of NE and 5-HT on XII motoneurons are mediated by a 1 -adrenergic and 5-HT 2A receptors that are abundantly expressed in XII motoneurons (9,(21)(22)(23).…”

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

“…Previous OSA drug candidates have generally targeted various excitatory receptors on hypoglossal motoneurons (HMs, also known as XII neurons) supplying the upper airway dilator muscles (11)(12)(13). However, related preclinical and clinical studies to date have been disappointing (8)(9)(10).…”

“…One major difficulty with a noradrenergic-based therapy for OSA is that the influence of endogenous noradrenergic drive on HM activity has proved highly complex and cannot be mimicked by direct activation of HMs with exogenous adrenergic drugs, particularly during REM sleep (12,13). In particular, recent studies reveal that repetitive obstructive apnea per se may elicit persistent facilitation of rat GG activity, a form of vagally mediated neuroplasticity (referred to as hypoglossal long-term facilitation, hLTF) that requires the activation of α 1 -adrenoceptors on HMs for its expression (24).…”