help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on August 24, 2006, doi:10.1164/rccm.200605-597OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200605-597OCv1
174/11/1264    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chan, E.
Right arrow Articles by Horner, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chan, E.
Right arrow Articles by Horner, R. L.
American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 1264-1273, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200605-597OC

Original Article

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

Erin Chan, Hendrik W. Steenland, Hattie Liu and Richard L. Horner

Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Richard L. Horner, Ph.D., Room 6368 Medical Sciences Building, 1 Kings College Circle, Toronto, ON, Canada M5S 1A8. E-mail: richard.horner{at}utoronto.ca


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: 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.

Objectives: We determined if {alpha}1 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 {alpha}1 receptor stimulation could counteract reduced endogenous noradrenergic drive and increase sleeping GG activity.

Methods: 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.

Measurements and Main Results: Microdialysis perfusion of the {alpha}1 receptor antagonist terazosin into the HMN significantly decreased GG activity in wakefulness and nonrapid eye movement (non-REM) sleep but not REM sleep. The {alpha}1 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 {alpha}1 and 5-HT2 receptor stimulation.

Conclusions: 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.

Key Words: genioglossus muscle • hypoglossal motor nucleus • noradrenaline • obstructive sleep apnea • serotonin • sleep



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Suppression of respiratory muscle activity in sleep is central to the pathogenesis of sleep-disordered breathing. However, the mechanisms modulating respiratory muscle activity across sleep–wake states had not been determined.

What This Study Adds to the Field
We identify an endogenous excitatory drive contributing to the maintenance of respiratory muscle activity in wakefulness and sleep. This article also has wider implications to other clinical problems of motor control in sleep, e.g., narcolepsy.

 
A characteristic feature of mammalian sleep is decreased postural muscle tone, especially in rapid-eye-movement (REM) sleep (1). This suppression of motor activity also occurs in respiratory muscles, particularly in those that combine postural and respiratory functions, such as the intercostal (2) and pharyngeal muscles (3). Decreased respiratory muscle activity occurs immediately at sleep onset (4, 5) and across sleep–wake states during constant mechanical ventilation (6), indicating a primary suppressant effect of sleep mechanisms on respiratory motor activity. The concept of a tonic excitatory drive activating respiratory muscle in wakefulness that is then withdrawn in sleep (i.e., the "wakefulness stimulus" to breathing) 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 common sleep-related breathing disorders (7, 8). However, the potential neurotransmitter substrates comprising this endogenous sleep-state dependent drive to respiratory motoneurons have not been determined.

The National Commission on Sleep Disorders Research has identified sleep disorders as a major public health burden affecting millions of North Americans (9). Understanding the physiologic processes that control muscle activity in sleep is important because abnormal regulation underlies several major sleep disorders, such as obstructive sleep apnea (OSA), narcolepsy, and REM sleep behavior disorder. OSA is the most common and serious of these sleep disorders (10) and affects approximately 2% of women and 4% of men (11). OSA is characterized by repeated closure of the pharyngeal airspace during sleep, resulting in periodic interruptions of airflow and pulmonary gas exchange and bouts of asphyxia, with these events terminated by arousal from sleep (12). Airway obstructions can occur hundreds of times a night in patients with OSA, causing disrupted sleep patterns and excessive daytime sleepiness, with impaired alertness leading to increased work-related and motor vehicle accidents (13). OSA also plays an important role in the development of cardiovascular diseases (14), including daytime hypertension (15), and contributes to premature death (16). Because obstructive apneas occur only during sleep and not during wakefulness, the aim of this study was to determine the underlying neural mechanisms contributing to pharyngeal muscle activation during wakefulness and sleep.

We have developed an animal model for manipulation of neurotransmission at the hypoglossal motor nucleus (HMN) in the caudal medulla of freely behaving rats (17) to determine mechanisms modulating motor outflow to the genioglossus (GG) muscle of the tongue across natural sleep–wake states. The GG was investigated as the model respiratory muscle because it plays a significant role in maintaining an open airspace for effective breathing and preventing OSA (12). Noradrenaline depolarizes and increases the excitability of hypoglossal motoneurons in brainstem tissue slices studied in vitro via {alpha}1 adrenergic receptor mechanisms (18–20). In intact animals, brainstem noradrenaline-containing neurons show declining discharge rates from wakefulness to non-REM and REM sleep (21). We tested the hypothesis that {alpha}1 receptor antagonism at the HMN decreases GG activity in a manner consistent with a significant role for endogenous noradrenergic mechanisms contributing to GG activation across sleep–wake states. We also tested the hypothesis that if withdrawal of noradrenergic inputs contributes to decreased GG activity in sleep, then application of an {alpha}1 receptor agonist should counteract this effect and increase sleeping GG activity to waking levels, a result with potential clinical relevance to pharmacologic strategies for the treatment of OSA. Finally, given the stimulating effects of 5-hydroxytraptamine (5-HT) at the HMN in vivo (17, 22) we determined if responses to combined {alpha}1 and 5-HT receptor stimulation at the HMN were additive. Some of the results of this study have been reported in the form of an abstract (23, 24).


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A more detailed account of the methods is given in the on-line supplement. Experiments were performed on 32 male Wistar rats (mean body weight, 270.8 g). Procedures conformed to the recommendations of the Canadian Council on Animal Care, and the University of Toronto Animal Care Committee approved the protocols.

Surgical Procedures
Sterile surgery was performed under general anesthesia for the chronic implantation of EEG and neck EMG electrodes to determine sleep–wake states and GG and diaphragm wires for respiratory muscle recordings (25, 26). Microdialysis guides were targeted 3 mm above the HMN (25, 26). The rats recovered for an average of 7.0 d (range, 6–8 d) before the experiments.

Protocol
On the day of the experiment, the microdialysis probe was inserted into the HMN and flushed with artificial cerebrospinal fluid (ACSF; pH, 7.40 ± 0.003) at a flow rate of 2.1 µl/min. At least 45 min were allowed to elapse before sleep–wake states and respiratory muscle activities were analyzed (25, 26). At least two full sleep cycles (i.e., periods containing quiet wakefulness, non-REM sleep, and REM sleep) elapsed before switching the perfusion medium; data were not analyzed for at least 45 min after the switch.

Study 1: {alpha}1 receptor antagonism at the HMN.
Experiments were performed in 10 rats to determine if an endogenous {alpha}1-mediated tonic excitatory drive contributes to GG activation across sleep-wake states. Respiratory muscle activities were recorded during perfusion of ACSF into the HMN followed by terazosin dissolved in 1.0 mM ACSF (pH, 7.39 ± 0.026; Sigma, St. Louis, MO). Terazosin is a specific antagonist for {alpha}1 receptors (27, 28). In initial experiments in three urethane-anesthetized rats with the vagus nerves intact, using methods previously described (29), 1 mM terazosin abolished the robust increases in GG activity produced by 1 mM of the {alpha}1 receptor agonist phenylephrine (see RESULTS).

Study 2: {alpha}1 receptor stimulation at the HMN.
Experiments in a separate group of 10 rats were performed to determine if {alpha}1 receptor stimulation at the HMN would increase GG activity across sleep–wake states. Respiratory muscle activities were recorded during perfusion of ACSF at the HMN followed by 1.0 mM phenylephrine (pH, 7.51 ± 0.012; Sigma). In initial experiments in two urethane-anesthetized rats, this dose of phenylephrine produced robust increases in GG activity, and similar robust responses occurred in the conscious rats (see RESULTS).

Study 3: combined {alpha}1 and 5-HT2 receptor stimulation.
Experiments were performed to determine if responses to combined {alpha}1 and 5-HT receptor stimulation at the HMN were additive. For these studies, 1 mM phenylephrine and 0.1 mM of the 5-HT2 receptor agonist {alpha}-methyl-5-HT maleate ({alpha}-Me-5-HT; Sigma) were applied to the HMN, first alone then in combination. The order of application was balanced and varied between experiments. In an initial group of six rats, perfusion of ACSF into the HMN was followed by phenylephrine (pH, 7.50 ± 0.008), which was maintained across sleep–wake states before the phenylephrine was applied in combination with {alpha}-Me-5-HT (pH, 7.55 ± 0.029). In a separate group of six rats, ACSF at the HMN was followed by a switch to {alpha}-Me-5-HT (pH, 7.46 ± 0.022), which was maintained across sleep–wake states before phenylephrine was applied in the continuing presence of the {alpha}-Me-5-HT (pH, 7.57 ± 0.016).

Tests for Each Experiment and Data Analysis
To confirm that the HMN was functional and able to respond to manipulation of neurotransmission at the end of each experiment, 10 mM of 5-HT was applied to the HMN as a positive control to document the expected increase in GG activity (25, 26). Microdialysis sites were confirmed by histology (25, 26).

Sleep–wake states and respiratory muscle activities were analyzed as previously described (25, 26) and outlined in the on-line supplement. Statistics were performed using ANOVA with repeated measures (ANOVA-RM), and post hoc t tests were performed using Bonferroni corrected p values. All data are expressed as mean ± SEM.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Location of Microdialysis Probes and Hypoglossal Motor Function
Figure 1A shows an example of a lesion site made by a microdialysis probe in the HMN in one rat. Figure 1 also shows the distribution of individual microdialysis sites from all rats administered terazosin, phenylephrine, and combined phenylephrine and {alpha}-Me-5-HT. Microdialysis probes were successfully implanted into, or immediately adjacent to, the HMN in all animals. Tongue movement occurred in each rat in response to electrical stimulation of the GG electrodes at the time of surgery and after the experiments, showing that these electrodes were in place throughout the study. Each rat showed consistent GG responses to 5-HT at the HMN at the end of the experiments, indicating an intact HMN during the study (25, 26). The rats had returned to their presurgical weights at the time of the experiments (270.8 ± 2.4 vs. 270.5 ± 3.1 g; t31 = 0.116; p = 0.908, paired t test).


Figure 1
View larger version (80K):
[in this window]
[in a new window]
  		Figure 1. Example and group data showing location of the microdialysis probes. (A) Histologic section showing an example of a lesion site made by the microdialysis probe immediately adjacent to both hypoglossal motor nuclei. Also shown are the distribution of individual microdialysis sites from all rats administered terazosin (B), phenylephrine (C), and combined phenylephrine and {alpha}-Me-5-HT (D). The sizes of the bars represent the apparent size of the lesions from the histologic sections. AP = area postrema; Cer = cerebellum; HMN = hypoglossal motor nucleus; Sol = nucleus of the tractus solitarius; 4V = fourth ventricle.

 
Study 1: {alpha}1 Receptor Antagonism at the HMN
With the exception of two rats that did not have REM sleep with terazosin, periods of wakefulness, non-REM sleep, and REM sleep were analyzed in all animals. In the 10 rats, a total of 9,834 5-s periods (i.e., 13.7 h of data) were analyzed, of which 7.4% were from wakefulness, 75.4% were from non-REM sleep, and 17.3% were from REM sleep. Figure 2A shows an example of GG responses to microdialysis perfusion of terazosin into the HMN. Compared with ACSF control animals, terazosin reduced respiratory-related and tonic GG activities in wakefulness and reduced respiratory-related GG activity in non-REM sleep. GG activity was lowest in REM sleep, and there was no subsequent effect of terazosin. Figure 2B shows the efficacy of 1 mM terazosin in abolishing the robust increases in GG activity produced by 1 mM of the {alpha}1 receptor agonist phenylephrine.


Figure 2
View larger version (22K):
[in this window]
[in a new window]
  		Figure 2. Example showing the effects of {alpha}1 receptor antagonism at the HMN on genioglossus (GG) muscle activity across sleep–wake states. (A) Traces show the EEG, neck EMG, GG, and diaphragm (Dia) EMG signals. The GG and Dia are also displayed as their moving-time averages (MTA) in arbitrary units (AU). The baseline of the integrator (i.e., electrical zero) is shown for the GG MTA. Compared with artificial cerebrospinal fluid (ACSF) controls, terazosin reduced respiratory-related and tonic GG activities in wakefulness and reduced respiratory-related GG activity in non-REM sleep. GG activity was lowest in REM, sleep and there was no subsequent effect of terazosin. (B) The traces show that 1 mM terazosin (TER) was sufficient to abolish the robust increases in GG activity produced by 1 mM of the {alpha}1 receptor agonist phenylephrine (PE).

 
GG responses: group data.
Figure 3A shows the effects of terazosin at the HMN on respiratory-related GG activity compared with ACSF control animals and illustrates that the effects of terazosin were dependent on the prevailing sleep–wake state (F2,16 = 11.57; p < 0.001, ANOVA-RM). Terazosin decreased respiratory-related GG activity in wakefulness (t9 = 4.00, p < 0.001, post hoc paired t test) and non-REM sleep (t9 = 2.60; p = 0.018) but not in REM sleep (t7 = 1.21; p = 0.242), which is consistent with the presence of a functional {alpha}1 receptor– mediated excitatory drive to the HMN contributing to GG muscle activation in wakefulness and non-REM sleep but not REM sleep. Analyses also showed that the normal significant decline in respiratory-related GG activity from non-REM to REM sleep with ACSF at the HMN (t7 = 3.49; p = 0.005, post hoc paired t test) was not present with terazosin (t7 = 0.35; p = 1.00). This latter result further illustrates that the levels of GG activity in non-REM sleep were maintained chiefly by noradrenergic mechanisms because, when antagonized by terazosin, GG activity was lowered to levels that were now not statistically different from the minimal levels observed in REM sleep (Figures 2 and 3A).


Figure 3
View larger version (9K):
[in this window]
[in a new window]
  		Figure 3. Group mean data showing reduced respiratory-related and tonic GG muscle activities with {alpha}1 receptor antagonism at the HMN. (A) Terazosin decreased respiratory-related GG in wakefulness and non-REM sleep but not in REM sleep. (B) Terazosin decreased tonic GG activity in wakefulness only. *p < 0.05 for terazosin (gray bars) compared with ACSF controls (black bars). Data are mean ± SEM.

 
Figure 3B illustrates that terazosin at the HMN decreased tonic GG activity, with this effect also dependent on prevailing sleep-wake state (F2,16 = 6.89; p = 0.007); terazosin decreased tonic GG activity in wakefulness (t9 = 3.22; p = 0.004, post hoc t test) but not in non-REM (t9 = 0.644; p = 0.527) or REM sleep (t7 = 0.10; p = 0.922). The normal significant decline in tonic GG activity from wakefulness to non-REM sleep with ACSF at the HMN (t9 = 3.18; p = 0.010) was not present with terazosin (t9 = 0.57; p = 1.00), illustrating that levels of tonic GG activity in wakefulness were maintained largely by noradrenergic mechanisms that, when antagonized, lowered tonic GG activity to sleeping levels (Figure 3B).

Specificity of responses.
Responses to terazosin at the HMN were specific to GG because there were no independent effects on respiratory rate (F1,9 = 0.46; p = 0.513, ANOVA-RM), diaphragm amplitude (F1,9 = 4.08; p = 0.074), or diaphragm minute activity (i.e., respiratory rate x diaphragm amplitude, F1,9 = 3.13; p = 0.110). Individual values of respiratory rate in the presence of ACSF at the HMN were 93.8 ± 3.9, 88.1 ± 3.9, and 111.8 ± 3.0 breaths per minute in wakefulness, non-REM sleep, and REM sleep, and were 92.5 ± 3.8, 90.7 ± 4.9, and 111.5 ± 4.5, respectively, in the presence of terazosin. Individual values of diaphragm amplitude with ACSF at the HMN were 104.8 ± 17.7, 114.4 ± 21.3, and 115.2 ± 21.9 arbitrary units in wakefulness, non-REM sleep, and REM sleep, and were 102.6 ± 20.2, 100.6 ± 22.6, and 100.8 ± 27.6, respectively, in the presence of terazosin. EEG frequencies from 0.5 to 30 Hz and the ratio of high (20–30 Hz) to low (0.5–2 Hz) frequency activity (25, 26) were also not different between terazosin and ACSF (all F1,9 < 2.31; p > 0.159). Neck EMG activity with terazosin was different from ACSF (F1,9 = 7.35; p = 0.023), an effect that was dependent on sleep–wake state (F2,16 = 11.74; p < 0.001). A significant decrease in the level of neck EMG activity was recorded in the awake periods with terazosin at the HMN (t9 = 5.66; p < 0.001, post hoc paired t test), but no differences were observed in non-REM (t9 = 0.30; p = 0.767) or REM sleep (t8 = 0.09; p = 0.927).

Study 2: {alpha}1 Receptor Stimulation at the HMN
With the exception of one rat that did not have REM sleep with phenylephrine, periods of wakefulness, non-REM sleep, and REM sleep were analyzed in all 10 animals. A total of 10,970 5-s epochs (i.e., 15.2 h of data) were analyzed, of which 5.6% were from wakefulness, 73.7% were from non-REM sleep, and 20.7% were from REM sleep. Figure 4 shows an example of GG responses to microdialysis perfusion of phenylephrine into the HMN. Compared with ACSF control animals, phenylephrine increased the respiratory-related and tonic components GG activity in wakefulness, non-REM sleep, and REM sleep. The brief GG twitches observed in REM sleep with ACSF are typical and have been observed previously in rats (25, 26) and in other species (30) and are thought to be responsible for the periodic improvements in airway patency (31) and restorations of airflow during obstructive apneas during REM sleep in humans (32). Figure 4 shows that such phasic GG events in REM sleep were augmented by phenylephrine at the HMN. Figure 5 further illustrates that, although the phasic GG events in REM sleep were augmented in the presence of phenylephrine, the {alpha}1 receptor stimulation was unable to overcome the episodes of major suppression of GG activity that accompany periods of REM sleep. This augmentation of the transient bursts of GG activity by phenylephrine was responsible for the overall increases in GG activity in REM sleep.


Figure 4
View larger version (17K):
[in this window]
[in a new window]
  		Figure 4. Example showing the effects of {alpha}1 receptor stimulation at the HMN on GG activity. Compared with ACSF, phenylephrine increased GG activity in wakefulness, non-REM sleep, and REM sleep, with the latter due to augmentation of the transient GG activations typical of REM sleep (see text for further details).

 

Figure 5
View larger version (18K):
[in this window]
[in a new window]
  		Figure 5. Example showing the major suppression of GG activity at the onset and during periods of REM sleep despite the continuing presence of phenylephrine at the HMN. The suppression of GG activity at the transition from non-REM to REM sleep and the later variations in GG activity associated with transient GG activations in REM sleep are readily apparent (see text for further details).

 
GG responses: group data.
Figure 6A shows that there was a significant stimulating effect of phenylephrine on respiratory-related GG activity (F1,9 = 12.03; p = 0.007, ANOVA-RM) that did not depend on the prevailing sleep–wake state (F2,17 = 0.926; p = 0.415). Figure 6B shows that phenylephrine also increased tonic GG activity (F1,9 = 16.62; p = 0.003); this effect was not dependent on sleep–wake state (F2,17 = 2.07; p = 0.157).


Figure 6
View larger version (11K):
[in this window]
[in a new window]
  		Figure 6. Group mean data showing increased respiratory-related (A) and tonic (B) GG activities across sleep–wake states with {alpha}1 receptor stimulation at the HMN. *p < 0.05 for phenylephrine (gray bars) compared with ASCF controls (black bars).

 
Specificity of responses.
Responses to phenylephrine at the HMN were specific to the GG muscle because there were no independent effects on respiratory rate (F1,9 = 0.42; p = 0.535, ANOVA-RM), diaphragm amplitude (F1,9 = 0.06; p = 0.817), or diaphragm minute activity (F1,9 = 0.18; p = 0.681). Individual values of respiratory rate in the presence of ACSF at the HMN were 95.3 ± 2.1, 87.2 ± 3.3, and 107.9 ± 2.0 breaths per minute in wakefulness, non-REM sleep, and REM sleep, and were 89.1 ± 3.2, 87.9 ± 2.7, and 110.9 ± 2.4, respectively, in the presence of phenylephrine. Individual values of diaphragm amplitude with ACSF at the HMN were 115.2 ± 25.7, 126.8 ± 27.0, and 123.8 ± 25.9 arbitrary units in wakefulness, non-REM sleep, and REM sleep, and were 116.4 ± 25.1, 129.0 ± 29.2, and 128.0 ± 32.2, respectively, in the presence of phenylephrine. EEG frequencies from 0.5 to 30 Hz and the ratio of high (20–30 Hz) to low (0.5–2 Hz) frequency activity were also not different between phenylephrine and ACSF (all F1,9 < 3.55; p > 0.091), except for a small increase (mean = 0.88%) in EEG activity in the beta1 (13.5–20 Hz) frequency band in the presence of phenylephrine. Phenylephrine at the HMN had no independent effect on neck EMG activity (F1,9 = 3.99; p = 0.076). Nevertheless, neck EMG was altered in the presence of phenylephrine depending on sleep–wake state (F2,17 = 5.94, p = 0.011); neck EMG activity was decreased in the awake periods during phenylephrine (t9 = 4.01; p < 0.001, post hoc paired t test), but no differences occurred in non-REM or REM sleep (t9 < 0.20; p > 0.847).

Study 3: Effects of Combined {alpha}1 and 5-HT2 Receptor Stimulation
The group data in Figure 7 show the effects of individual and combined {alpha}1 and 5-HT2 receptor stimulation at the HMN on respiratory-related and tonic GG activities. This figure illustrates that there was no significant difference between the levels of GG activity recorded during combined {alpha}1 and 5-HT2 receptor stimulation at the HMN compared with the sum of the two independent responses (all p > 0.200, paired t tests) (i.e., evidence that the responses were additive). The only exception was lower GG activity in REM sleep when phenylephrine was combined with {alpha}-Me-5-HT, compared with the sum of the two independent responses (p < 0.011, paired t test; Figure 7). However, not all rats had REM sleep during the time of combined drug administration because of the expanded length of the experiments with these additional interventions; therefore, this significant decrease may have been biased by the fewer rats in the analysis.


Figure 7
View larger version (29K):
[in this window]
[in a new window]
  		Figure 7. Group data showing responses to {alpha}1 and {alpha}-Me-5-HT (5-HT2) receptor stimulation at the HMN. The bars show the mean (± SEM) change in respiratory-related and tonic GG activities from ACSF in response to individual and combined phenylephrine (PE) and 5-HT at the HMN. The calculated summed responses to the individual PE and 5-HT interventions are also shown for each sleep–wake state (dashed lines). All values are derived from responses in six animals unless otherwise indicated. *Significant difference (p < 0.05) in the response to combined PE and 5-HT compared with the calculated summed responses from the individual interventions.

 
Figure 8 illustrates that although the overall transient GG activations in REM sleep were augmented in the presence of phenylephrine and {alpha}-Me-5-HT at the HMN, the combined {alpha}1 and 5-HT2 receptor stimulation was unable to overcome the occasional periods of clear suppression of GG activity that accompany episodes of REM sleep.


Figure 8
View larger version (14K):
[in this window]
[in a new window]
  		Figure 8. Example showing the episodes of major suppression of GG activity at the onset and during periods of REM sleep despite the continuing presence of combined phenylephrine and {alpha}-Me-5-HT at the HMN. For the phenylephrine + {alpha}-Me-5-HT and the ACSF traces, the suppression of GG activity at the transition from non-REM to REM sleep and the later variations in GG activity associated with transient GG activations in REM sleep are apparent (see text for further details).

 

   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study is the first to identify a neurotransmitter substrate that contributes significantly to respiratory muscle activation across sleep–wake states. The concept of an endogenous noradrenergic drive contributing to GG muscle activation in wakefulness and non-REM sleep, but not REM sleep, is important given the prevalence and clinical significance of sleep-induced hypoventilation and OSA in humans (9–11) and the long-standing concept of a "wakefulness stimulus" to breathing whose neurochemical basis had not been previously determined (7, 8).

Responses in Wakefulness
The decrease in respiratory-related and tonic GG activity after {alpha}1 receptor antagonism at the HMN in wakefulness indicates the presence of a functional endogenous noradrenergic drive to this motoneuronal pool when awake. This result is in keeping with the known discharge of brainstem noradrenergic neurons, which is highest in wakefulness (21), and the projection of such neurons to the HMN (33, 34). That {alpha}1 receptor antagonism decreased tonic and respiratory-related components of GG activity is also consistent with {alpha}1 receptor mechanisms affecting membrane potential and excitability of hypoglossal motoneurons in vitro (18–20). Nevertheless, GG activity was not abolished after {alpha}1 receptor antagonism (see Figure 2), indicating that other neurotransmitters contribute to GG motor activation when awake. Recent studies suggest that endogenous 5-HT (26) and serotonergic raphe neurons (35) are not a major source of excitatory drive to GG muscle across sleep–wake states, at least in this intact, freely behaving animal model. The contribution other state-dependent neurotransmitters, such as glutamate and acetylcholine, remains to be determined in conscious animals, but potentially relevant responses have been observed in vitro (36–38) and in anesthetized animals in vivo (29, 39).

That {alpha}1 receptor mechanisms contribute to respiratory-related and tonic components of GG activation in wakefulness is relevant because these components contribute to the maintenance of airway patency via effects on airway size and collapsibility (31, 40, 41). The effects on tonic GG activity are especially relevant because, unlike phrenic motoneurons, hypoglossal motoneurons are not inhibited throughout expiration (42–44); therefore, expiratory activity is the manifestation of prevailing tonic inputs that are revealed when inspiratory activation is withdrawn. Because the results of the present study show that noradrenergic mechanisms contribute significantly to tonic GG activity in wakefulness, then reduced tonic GG activity in sleep (45–47), especially during REM sleep when noradrenergic neuronal activity is minimal (21), would increase the vulnerability of the pharyngeal airspace to collapse.

Non-REM and REM Sleep
Non-REM sleep was characterized by respiratory-related GG activity and minimal tonic activity (see Figure 2), a pattern also observed in humans (3, 4, 48). The levels of respiratory-related GG activity in non-REM sleep were maintained chiefly by noradrenergic mechanisms because {alpha}1 receptor antagonism decreased this activity to levels similar to those observed in REM sleep. An endogenous noradrenergic drive contributing to the maintenance of respiratory-related GG activity in non-REM sleep is consistent with continuing discharge of brainstem noradrenergic neurons in sleep, albeit at a lower level than when awake (21).

That respiratory-related GG activity in sleep was minimal after {alpha}1 receptor antagonism at the HMN and that there was no subsequent statistically significant change from non-REM to REM sleep implicates withdrawal of endogenous noradrenergic inputs to the HMN as a major contributor to periods of GG motor atonia in REM sleep. This result is consistent with the concept that the endogenous activating effects of noradrenaline at the HMN would be withdrawn in REM sleep because brainstem noradrenergic neuronal activity is minimal (21). This result is clinically relevant because, until this study, the neural mechanisms responsible for periods of suppression of respiratory-related GG activity in natural REM sleep had not been determined; we recently showed that inhibition mediated via glycine and {gamma}-amino-butyric acid and disfacilitation via 5-HT play only a minor role at the HMN in intact, conscious, freely behaving animals (25, 26, 49).

The results showing a significant role for {alpha}1 receptor mechanisms mediating suppression of respiratory-related GG activity in REM sleep fits with a recent study using a pharmacologic model of "REM sleep" in anesthetized rats (50). In that study, microinjection of the cholinergic agonist carbachol into the pontine reticular formation of anesthetized and vagotomized rats was associated with withdrawal of noradrenergic inputs to the HMN and suppression of respiratory-related hypoglossal nerve activity (50). During anesthesia before carbachol, {alpha}1 receptor antagonism at the HMN decreased respiratory-related hypoglossal nerve activity, indicating that hypoglossal motoneurons are influenced by an endogenous excitatory noradrenergic drive, which is consistent with our results in intact conscious animals in wakefulness and non-REM sleep. Moreover, after {alpha}1 receptor antagonism, pontine carbachol no longer caused depression of hypoglossal nerve activity (50), which is consistent with our results showing that respiratory-related GG activity did not change from non-REM to REM sleep after terazosin. In a separate study in decerebrate cats, electrical or cholinergic stimulation of the pontine reticular formation reduced GG activity and noradrenaline levels at the HMN (51), which is consistent with the notion that suppression of respiratory-related GG activity after activation of the REM sleep triggering region is associated with reduced noradrenergic inputs to the HMN.

Responses to {alpha}1 Receptor Stimulation
Given the concept that an {alpha}1 receptor–mediated endogenous excitatory drive contributes to the maintenance of GG activity across sleep–wake states, an additional study was performed to determine if application of an {alpha}1 receptor agonist could counteract the sleep-related decrease in GG activity. In agreement with the hypothesis, phenylephrine at the HMN increased tonic and respiratory-related GG activity in wakefulness, non-REM sleep, and REM sleep (see Figure 6), a result potentially relevant to pharmacologic strategies aiming to increase GG activity in sleep as a treatment for OSA (52, 53). Moreover, combined {alpha}1 and 5-HT2 receptor stimulation at the HMN increased GG activity across sleep–wake states to levels greater than when each agonist was applied alone, and there was evidence for an additive effect at least at the single doses tested (see Figure 7). This result may have relevance to studies aiming to increase pharyngeal muscle activity by manipulating 5-HT and noradrenergic neurotransmission (e.g., by agonists or serotonin–norepinephrine reuptake inhibitors) where combined effects may have more benefit than manipulating a single neurotransmitter system.

Although {alpha}1 receptor stimulation at the HMN increased GG activity in wakefulness, non-REM sleep, and REM sleep, phenylephrine was unable to overcome the episodes of major suppression of GG activity in periods of REM (see Figure 5). Similar major attenuation of GG motor responses in REM sleep occur with delivery of 5-HT to the HMN (17) and during combined {alpha}1 and 5-HT2 receptor stimulation (Figure 8). These data highlight the finding that {alpha}1 and 5-HT receptor stimulation at the HMN have differential effects on motor output to GG muscle depending on the prevailing sleep–wake states, further emphasizing that responses observed under constant conditions in reduced preparations (18, 19, 22) are not intractable but are significantly modulated by ongoing behavioral states in conscious preparations. Once the distinct mechanisms underlying the control of pharyngeal muscle activity in REM sleep have been identified, the results of the present study suggest that a combination of pharmacologic approaches may be the most effective approach to achieve sustained increases in GG activity because different neural mechanisms are operative in non-REM and REM sleep.

The inability to overcome the periodic episodes of motor suppression in REM sleep further suggests that attempted pharmacologic manipulations of these monoaminergic neurotransmitter systems may have limited clinical benefit as treatment for OSA. Initial clinical studies in patients with OSA suggest this may be the case for the 5-HT agents tested (54–59), but comparable studies have not been reported for adrenergic agents. The neural mechanisms responsible for the marked attenuation of GG motor responses to {alpha}1 and 5-HT receptor stimulation at the HMN in periods of REM sleep have not been identified. However, the abolition of otherwise robust excitatory GG motor responses to these applied neurotransmitters also occurs with increased cyclic guanosine-3'-5'-monophosphate at the HMN, an effect that may be linked to REM sleep mechanisms via nitric oxide (60).

Despite the periods of major motor suppression in REM sleep, {alpha}1 receptor stimulation at the HMN with phenylephrine led to overall increases in GG activity due to augmentation of the sporadic bursts of GG activity in REM sleep (see Figure 5), as has been observed with 5-HT at the HMN (17). This result was expected because the transient motor activations in REM sleep are believed to be mediated by glutamatergic inputs (61) and responses to glutamate are augmented in the presence of {alpha}1 and 5-HT receptor stimulation (62). Although the transient bursts of GG muscle activity in REM sleep are believed to be responsible for the periodic improvements in airway patency in REM sleep and OSA (31, 32), the clinical relevance of augmenting such sporadic pharyngeal muscle activations is unclear and may destabilize the upper airway by uncoupling the coordinated activation of the pharyngeal muscles during breathing.

Although phenylephrine and terazosin at the HMN did not alter respiratory rate, diaphragm activity, or EEG frequencies, suggesting that responses were specific to effects at the HMN, a decrease in neck EMG activity occurred in the presence of phenylephrine and terazosin. Unlike the GG responses, however, this effect was confined to wakefulness and did not persist into non-REM or REM sleep. This observation, combined with the same direction of change in neck EMG in the presence of the {alpha}1 receptor agonist and antagonist at the HMN, suggested that the changes in neck EMG were likely due to a nonspecific epiphenomenon rather than being a specific effect of phenylephrine or terazosin per se.

Functional Noradrenergic Drive to Motoneurons and Wider Implications
This study addressed the modulation of a model respiratory muscle across sleep–wake states and demonstrated a functional endogenous {alpha}1 receptor–mediated drive stimulating motor activity. There are widespread projections of brainstem catecholaminergic neurons with sleep-state–dependent activity, although not all have been tested for sleep-state–dependent activity. Noradrenergic neurons of the locus coeruleus and subcoeruleus show robust decrements in activity from wakefulness to non-REM and REM sleep (21, 63). The main noradrenergic innervation of the HMN arises from subcoeruleus neurons (33, 64), with locus coeruleus neurons projecting primarily to sensory and association nuclei of the brainstem and not motor nuclei (65). Although A7 neurons also have significant projections to the HMN (33), the sleep-state–dependent activity of these neurons is not well studied. A5 neurons show decreased activity in the REM sleep–like state elicited by pontine carbachol, but a sample of those neurons showed that none projected to hypoglossal motoneurons (66). Accordingly, the weight of evidence suggests that subcoeruleus and perhaps A7 neurons are the likely source of the endogenous excitatory noradrenergic drive modulating GG activity across sleep–wake states in this study.

Given the widespread projections of brainstem catecholaminergic neurons, they are also positioned to provide an endogenous input to other respiratory and nonrespiratory neurons and motoneurons and therefore influence ventilation or motor tone (62, 66, 67). Brainstem catecholaminergic neurons are also appropriately positioned to modulate autonomic nervous system neurons influencing sympathetic (63) and bronchial tones (68, 69) and therefore may contribute to their activities and physiologic functions across sleep–wake states. These normal physiologic functions may be adversely affected by repetitive cycles of intermittent hypoxia because oxidative injury of pontine noradrenergic neurons occurs in animal models of sleep apnea (70). This vulnerability of such noradrenergic neurons to hypoxia-induced cell damage (70) has further implications for sleep-disordered breathing because it may negatively affect the normal {alpha}1 receptor–mediated drive maintaining tonic and respiratory-related GG muscle tone. In contrast to chronic intermittent hypoxia, however, acute exposure to hypoxia and hypercapnia activates noradrenergic neurons, and this response is believed to contribute to respiratory motor activation (71, 72), whereas repetitive noradrenergic stimulation can produce long-term facilitation of respiratory motoneuron activity (73).

In narcoleptic dogs, the spontaneous reductions in postural muscle tone during cataplexy are associated with decreased firing of brainstem noradrenergic locus coeruleus neurons (74, 75). In addition, pharmacologic treatments for cataplexy include agents that increase synaptic concentrations of noradrenaline by blocking reuptake or {alpha}1-receptor–stimulating agents to increase postural motor tone (76, 77). These data fit with the concept of a functional noradrenergic drive contributing to the maintenance of muscle tone, as shown in this study for motoneurons innervating the GG muscle, which has dual respiratory and nonrespiratory functions. Similar involvement of reduced noradrenergic excitation at GG and other pharyngeal and respiratory muscles during cataplexy may also be related to the reports of impaired speech and sensations of an inability to breathe in patients with narcolepsy during such episodes (78).


   FOOTNOTES
 
Supported by the Canadian Institutes of Health Research (grant MT-15563).

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200605-597OC on August 24, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form May 3, 2006; accepted in final form August 24, 2006


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Chase MH, Morales FR. Control of motoneurons during sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3 ed. Philadelphia, PA; WB Saunders; 2000. pp. 155–168.
  2. Duron B, Marlot D. Intercostal and diaphragmatic electrical activity during wakefulness and sleep in normal unrestrained adult cats. Sleep 1980;3:269–280.[Medline]
  3. Sauerland EK, Harper RM. The human tongue during sleep: electromyographic activity of the genioglossus muscle. Exp Neurol 1976;51:160–170.[CrossRef][Medline]
  4. Worsnop C, Kay A, Pierce R, Kim Y, Trinder J. Activity of respiratory pump and upper airway muscles during sleep onset. J Appl Physiol 1998;85:908–920.[Abstract/Free Full Text]
  5. Mezzanotte WS, Tangel DJ, White DP. Influence of sleep onset on upper-airway muscle activity in apnea patients versus normal controls. Am J Respir Crit Care Med 1996;153:1880–1887.[Abstract]
  6. Horner RL, Kozar LF, Kimoff RJ, Phillipson EA. Effects of sleep on the tonic drive to respiratory muscle and the threshold for rhythm generation in the dog. J Physiol 1994;474:525–537.[Abstract/Free Full Text]
  7. Orem J. Respiratory neurons and sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia, PA; WB Saunders; 1994. pp. 177–193.
  8. Phillipson EA, Bowes G. 1986. Control of breathing during sleep. In: Cherniack NS, Widdicombe , editors. Handbook of physiology, section 3: the respiratory system, vol. II, control of breathing, part 2. Bethesda, MD: American Physiological Society; 1986. pp. 649–689.
  9. National Commission on Sleep Disorders Research. Wake up America: a national sleep alert. Washington, D.C.; US Government Printing Office; 1993.
  10. Phillipson EA. Sleep apnea: a major public health problem. N Engl J Med 1993;328:1271–1273.[Free Full Text]
  11. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–1235.[Abstract/Free Full Text]
  12. Remmers JE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978;44:931–938.[Free Full Text]
  13. George CF, Nickerson PW, Hanly PJ, Millar TW, Kryger MH. Sleep apnoea patients have more automobile accidents. Lancet 1987;2:447.[CrossRef][Medline]
  14. Leung RS, Bradley TD. Sleep apnea and cardiovascular disease. Am J Respir Crit Care Med 2001;164:2147–2165.[Free Full Text]
  15. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. J Clin Invest 1997;99:106–109.[Medline]
  16. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034–2041.[Abstract/Free Full Text]
  17. Jelev A, Sood S, Liu H, Nolan P, Horner RL. Microdialysis perfusion of 5-HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep-wake states in rats. J Physiol 2001;532:467–481.[Abstract/Free Full Text]
  18. Parkis MA, Bayliss DA, Berger AJ. Actions of norepinephrine on rat hypoglossal motoneurons. J Neurophysiol 1995;74:1911–1919.[Abstract/Free Full Text]
  19. Al-Zubaidy ZA, Erickson RL, Greer JJ. Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats. Pflugers Arch 1996;431:942–949.[Medline]
  20. Funk GD, Smith JC, Feldman JL. Development of thyrotropin-releasing hormone and norepinephrine potentiation of inspiratory-related hypoglossal motoneuron discharge in neonatal and juvenile mice in vitro. J Neurophysiol 1994;72:2538–2541.[Abstract/Free Full Text]
  21. Aston-Jones G, Bloom FE. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci 1981;1:876–886.[Abstract]
  22. Kubin L, Tojima H, Davies RO, Pack AI. Serotonergic excitatory drive to hypoglossal motoneurons in the decerebrate cat. Neurosci Lett 1992;139:243–248.[CrossRef][Medline]
  23. Chan E, Steenland HW, Liu H, Horner RL. Endogenous noradrenergic drive contributes to genioglossus muscle activation in wakefulness and non-REM sleep. Proc Am Thoracic Soc 2006;3:A316.
  24. Chan E, Steenland HW, Liu H, Horner RL. Identification of an endogenous noradrenergic drive to respiratory motoneurons across sleep-wake states. Can Respir J 2006;13:165.
  25. Morrison JL, Sood S, Liu H, Park E, Nolan P, Horner RL. Role of inhibitory amino acids in control of hypoglossal motor outflow to genioglossus muscle in naturally sleeping rats. J Physiol 2003;552:975–991.[Abstract/Free Full Text]
  26. Sood S, Morrison JL, Liu H, Horner RL. Role of endogenous serotonin in modulating genioglossus muscle activity in awake and sleeping rats. Am J Respir Crit Care Med 2005;172:1338–1347.[Abstract/Free Full Text]
  27. Kyncl JJ. Pharmacology of terazosin: an alpha 1-selective blocker. J Clin Pharmacol 1993;33:878–883.[Medline]
  28. Hancock AA, Buckner SA, Ireland LM, Knepper SM, Kerwin JF Jr. Actions of terazosin and its enantiomers at subtypes of alpha 1- and alpha 2-adrenoceptors in vitro. J Recept Signal Transduct Res 1995;15:863–885.[Medline]
  29. Liu X, Sood S, Liu H, Horner RL. Opposing muscarinic and nicotinic modulation of hypoglossal motor output to genioglossus muscle in rats in vivo. J Physiol 2005;565:965–980.[Abstract/Free Full Text]
  30. Richard CA, Harper RM. Respiratory-related activity in hypoglossal neurons across sleep-waking states in cats. Brain Res 1991;542:167–170.[CrossRef][Medline]
  31. Goh AS, Issa FG, Sullivan CE. Upper airway dilating forces during wakefulness and sleep in dogs. J Appl Physiol 1986;61:2148–2155.[Abstract/Free Full Text]
  32. Younes M. Contributions of upper airway mechanics and control mechanisms to severity of obstructive apnea. Am J Respir Crit Care Med 2003;168:645–658.[Abstract/Free Full Text]
  33. Aldes LD, Chapman ME, Chronister RB, Haycock JW. Sources of noradrenergic afferents to the hypoglossal nucleus in the rat. Brain Res Bull 1992;29:931–942.[CrossRef][Medline]
  34. Travers JB, Norgren R. Afferent projections to the oral motor nuclei in the rat. J Comp Neurol 1983;220:280–298.[CrossRef][Medline]
  35. Sood S, Raddatz E, Liu X, Liu H, Horner RL. Inhibition of serotonergic medullary raphe obscurus neurons suppresses genioglossus and diaphragm activities in anesthetized but not conscious rats. J Appl Physiol 2006;100:1807–1821.[Abstract/Free Full Text]
  36. Greer JJ, Smith JC, Feldman JL. Role of excitatory amino acids in the generation and transmission of respiratory drive in neonatal rat. J Physiol 1991;437:727–749.[Abstract/Free Full Text]
  37. Funk GD, Smith JC, Feldman JL. Generation and transmission of respiratory oscillations in medullary slices: role of excitatory amino acids. J Neurophysiol 1993;70:1497–1515.[Abstract/Free Full Text]
  38. Bellingham MC, Funk GD. Cholinergic modulation of respiratory brain-stem neurons and its function in sleep-wake state determination. Clin Exp Pharmacol Physiol 2000;27:132–137.[CrossRef][Medline]
  39. Steenland HW, Liu H, Sood S, Liu X, Horner RL. Respiratory activation of the genioglossus muscle involves both non-NMDA and NMDA glutamate receptors at the hypoglossal motor nucleus in-vivo. Neuroscience 2006;138:1407–1424.[CrossRef][Medline]
  40. Kuna S, Remmers JE. Anatomy and physiology of upper airway obstruction. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia, PA; WB Saunders. pp. 840–858.
  41. Fuller DD, Williams JS, Janssen PL, Fregosi RF. Effect of co-activation of tongue protrudor and retractor muscles on tongue movements and pharyngeal airflow mechanics in the rat. J Physiol 1999;519:601–613.[Abstract/Free Full Text]
  42. Withington-Wray DJ, Mifflin SW, Spyer KM. Intracellular analysis of respiratory-modulated hypoglossal motoneurons in the cat. Neuroscience 1988;25:1041–1051.[CrossRef][Medline]
  43. Woch G, Kubin L. Non-reciprocal control of rhythmic activity in respiratory-modulated XII motoneurons. Neuroreport 1995;6:2085–2088.[Medline]
  44. Peever JH, Mateika JH, Duffin J. Respiratory control of hypoglossal motoneurones in the rat. Pflugers Arch 2001;442:78–86.[CrossRef][Medline]
  45. Tangel DJ, Mezzanotte WS, White DP. Influence of sleep on tensor palatini EMG and upper airway resistance in normal men. J Appl Physiol 1991;70:2574–2581.[Abstract/Free Full Text]
  46. Tangel DJ, Mezzanotte WS, Sandberg EJ, White DP. Influences of NREM sleep on the activity of tonic vs. inspiratory phasic muscles in normal men. J Appl Physiol 1992;73:1058–1066.[Abstract/Free Full Text]
  47. Horner RL. Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea. Sleep 1996;19:827–853.[Medline]
  48. Pillar G, Malhotra A, Fogel RB, Beauregard J, Slamowitz DI, Shea SA, White DP. Upper airway muscle responsiveness to rising PCO(2) during NREM sleep. J Appl Physiol 2000;89:1275–1282.[Abstract/Free Full Text]
  49. Morrison JL, Sood S, Liu H, Park E, Nolan P, Horner RL. GABA-A receptor antagonism at the hypoglossal motor nucleus increases genioglossus muscle activity in NREM but not REM sleep. J Physiol 2003;548:569–583.[Abstract/Free Full Text]
  50. Fenik VB, Davies RO, Kubin L. REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 2005;172:1322–1330.[Abstract/Free Full Text]
  51. Lai YY, Kodama T, Siegel JM. Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study. J Neurosci 2001;21:7384–7391.[Abstract/Free Full Text]
  52. Veasey SC. Pharmacotherapies for obstructive sleep apnea: how close are we? Curr Opin Pulm Med 2001;7:399–403.[CrossRef][Medline]
  53. Horner RL. The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea. Respir Res 2001;2:286–294.[CrossRef][Medline]
  54. Kraiczi H, Hedner J, Dahlof P, Ejnell H, Carlson J. Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea. Sleep 1999;22:61–67.[Medline]
  55. Sunderram J, Parisi RA, Strobel RJ. Serotonergic stimulation of the genioglossus and the response to nasal continuous positive airway pressure. Am J Respir Crit Care Med 2000;162:925–929.[Abstract/Free Full Text]
  56. Berry RB, Yamaura EM, Gill K, Reist C. Acute effects of paroxetine on genioglossus activity in obstructive sleep apnea. Sleep 1999;22:1087–1092.[Medline]
  57. Hanzel DA, Proia NG, Hudgel DW. Response of obstructive sleep apnea to fluoxetine and protriptyline. Chest 1991;100:416–421.[Abstract/Free Full Text]
  58. Veasey SC, Fenik P, Panckeri K, Pack AI, Hendricks JC. The effects of trazodone with L-tryptophan on sleep-disordered breathing in the English bulldog. Am J Respir Crit Care Med 1999;160:1659–1667.[Abstract/Free Full Text]
  59. Veasey SC, Chachkes J, Fenik P, Hendricks JC. The effects of ondansetron on sleep-disordered breathing in the English bulldog. Sleep 2001;24:155–160.[Medline]
  60. Aoki CR, Liu H, Downey GP, Mitchell J, Horner RL. Cyclic nucleotides modulate genioglossus and hypoglossal responses to excitatory inputs in rats. Am J Respir Crit Care Med 2006;173:555–565.[Abstract/Free Full Text]
  61. Soja PJ, Lopez-Rodriguez F, Morales FR, Chase MH. Effects of excitatory amino acid antagonists on the phasic depolarizing events that occur in lumbar motoneurons during REM periods of active sleep. J Neurosci 1995;15:4068–4076.[Abstract]
  62. Rekling JC, Funk GD, Bayliss DA, Dong XW, Feldman JL. Synaptic control of motoneuronal excitability. Physiol Rev 2000;80:767–852.[Abstract/Free Full Text]
  63. Reiner PB. Correlational analysis of central noradrenergic neuronal activity and sympathetic tone in behaving cats. Brain Res 1986;378:86–96.[CrossRef][Medline]
  64. Aldes LD. Topographically organized projections from the nucleus subceruleus to the hypoglossal nucleus in the rat: a light and electron microscopic study with complementary axonal transport techniques. J Comp Neurol 1990;302:643–656.[CrossRef][Medline]
  65. Aston-Jones G, Shipley MT, Grzanna R. The locus coeruleus, A5 and A7 noradrenergic cell groups. In: Paxinos G, editor. The rat nervous system. San Diego, CA: Academic Press; 1995. pp. 183–213.
  66. Fenik V, Marchenko V, Janssen P, Davies RO, Kubin L. A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol. J Appl Physiol 2002;93:1448–1456.[Abstract/Free Full Text]
  67. Li A, Nattie E. Catecholamine neurones in rats modulate sleep, breathing, central chemoreception and breathing variability. J Physiol 2006;570:385–396.[Abstract/Free Full Text]
  68. Haxhiu MA, Kc P, Neziri B, Yamamoto BK, Ferguson DG, Massari VJ. Catecholaminergic microcircuitry controlling the output of airway-related vagal preganglionic neurons. J Appl Physiol 2003;94:1999–2009.[Abstract/Free Full Text]
  69. Haxhiu MA, Rust CF, Brooks C, Kc P. CNS determinants of sleep-related worsening of airway functions: Implications for nocturnal asthma. Respir Physiol Neurobiol 2006;151:1–30.[CrossRef][Medline]
  70. Zhan G, Serrano F, Fenik P, Hsu R, Kong L, Pratico D, Klann E, Veasey SC. NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea. Am J Respir Crit Care Med 2005;172:921–929.[Abstract/Free Full Text]
  71. Elam M, Yao T, Thoren P, Svensson TH. Hypercapnia and hypoxia: chemoreceptor-mediated control of locus coeruleus neurons and splanchnic, sympathetic nerves. Brain Res 1981;222:373–381.[CrossRef][Medline]
  72. Ballantyne D, Scheid P. Mammalian brainstem chemosensitive neurones: linking them to respiration in vitro. J Physiol 2000;525:567–577.[Abstract/Free Full Text]
  73. Feldman JL, Neverova NV, Saywell SA. Modulation of hypoglossal motoneuron excitability by intracellular signal transduction cascades. Respir Physiol Neurobiol 2005;147:131–143.[CrossRef][Medline]
  74. John J, Wu MF, Boehmer LN, Siegel JM. Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 2004;42:619–634.[CrossRef][Medline]
  75. Wu MF, Gulyani SA, Yau E, Mignot E, Phan B, Siegel JM. Locus coeruleus neurons: cessation of activity during cataplexy. Neuroscience 1999;91:1389–1399.[CrossRef][Medline]
  76. Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat Neurosci 2002;5:1071–1075.
  77. Nishino S, Fruhstorfer B, Arrigoni J, Guilleminault C, Dement WC, Mignot E. Further characterization of the alpha-1 receptor subtype involved in the control of cataplexy in canine narcolepsy. J Pharmacol Exp Ther 1993;264:1079–1084.[Abstract/Free Full Text]
  78. Guilleminault C, Anagos A. Narcolepsy. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia, PA: WB Saunders; 2000. pp. 676–686.



This article has been cited by other articles:


Home page
 Phil Trans R Soc BHome page
R. L. Horner
Emerging principles and neural substrates underlying tonic sleep-state-dependent influences on respiratory motor activity
Phil Trans R Soc B, September 12, 2009; 364(1529): 2553 - 2564.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
A. Sanchez, S. Mustapic, E. J. Zuperku, A. G. Stucke, F. A. Hopp, and E. A. E. Stuth
Role of Inhibitory Neurotransmission in the Control of Canine Hypoglossal Motoneuron Activity In Vivo
J Neurophysiol, March 1, 2009; 101(3): 1211 - 1221.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
P. B. Schwarz, N. Yee, S. Mir, and J. H. Peever
Noradrenaline triggers muscle tone by amplifying glutamate-driven excitation of somatic motoneurones in anaesthetized rats
J. Physiol., December 1, 2008; 586(23): 5787 - 5802.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
D. V. Volgin, I. Rukhadze, and L. Kubin
Hypoglossal premotor neurons of the intermediate medullary reticular region express cholinergic markers
J Appl Physiol, November 1, 2008; 105(5): 1576 - 1584.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
H. W. Steenland, H. Liu, and R. L. Horner
Endogenous Glutamatergic Control of Rhythmically Active Mammalian Respiratory Motoneurons In Vivo
J. Neurosci., July 2, 2008; 28(27): 6826 - 6835.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. Burgess, D. Lai, J. Siegel, and J. Peever
An Endogenous Glutamatergic Drive onto Somatic Motoneurons Contributes to the Stereotypical Pattern of Muscle Tone across the Sleep-Wake Cycle
J. Neurosci., April 30, 2008; 28(18): 4649 - 4660.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
P. L. Brooks and J. H. Peever
Glycinergic and GABAA-Mediated Inhibition of Somatic Motoneurons Does Not Mediate Rapid Eye Movement Sleep Motor Atonia
J. Neurosci., April 2, 2008; 28(14): 3535 - 3545.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
Y. Zhu, P. Fenik, G. Zhan, E. Mazza, M. Kelz, G. Aston-Jones, and S. C. Veasey
Selective Loss of Catecholaminergic Wake Active Neurons in a Murine Sleep Apnea Model
J. Neurosci., September 12, 2007; 27(37): 10060 - 10071.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
S. Sood, X. Liu, H. Liu, and R. L. Horner
Genioglossus muscle activity and serotonergic modulation of hypoglossal motor output in obese Zucker rats
J Appl Physiol, June 1, 2007; 102(6): 2240 - 2250.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
R. L. Horner and T. D. Bradley
Update in Sleep and Control of Ventilation 2006
Am. J. Respir. Crit. Care Med., March 1, 2007; 175(5): 426 - 431.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200605-597OCv1
174/11/1264    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chan, E.
Right arrow Articles by Horner, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chan, E.
Right arrow Articles by Horner, R. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2006 American Thoracic Society