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(Chest. 1999;115:1397-1401.)
© 1999 American College of Chest Physicians

Role of Peripheral Serotonin in the Regulation of Central Sleep Apneas in Rats*

David W. Carley, PhD and Miodrag Radulovacki, MD, PhD

* From the Departments of Medicine (Dr. Carley) and Pharmacology (Drs. Carley and Radulovacki), University of Illinois College of Medicine at Chicago, Chicago, IL. Supported in part by National Institute on Aging grant AG14564.

Correspondence to: David W. Carley, PhD, Department of Medicine (M/C 787), University of Illinois, 840 S Wood St, Room 824, Chicago, IL 60612; e-mail: DWCarley{at}uic.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: The aim of our study was to determine the effects of serotonin (5-HT), which does not penetrate the blood-brain barrier (BBB), and GR38032F, a 5-HT3 receptor antagonist that may cross the BBB, on spontaneous apneas in adult Sprague-Dawley rats.

Measurements and results: Rats were implanted with electrodes for EEG and electromyographic recording to monitor sleep, with a radiotelemetry transmitter for monitoring aortic BP and heart period (HP) and were placed inside a single chamber plethysmograph for monitoring respiration. Sleep, BP, HP, and respiration were monitored for 6 h following administration of drugs. Intraperitoneal injection of 5-HT (0.79 mg/kg) to rats increased spontaneous central apneas during rapid eye movement (REM) sleep by > 250% in comparison to control recording (p = 0.01). GR38032F (0.1 mg/kg), which produced no effect on apnea expression, completely blocked the 5-HT-induced increase in REM apneas. Administration of 5-HT did not affect apnea expression in non-REM sleep and had no effect on sleep or BP.

Conclusions: From these observations, we conclude that binding at 5-HT3 receptors in the peripheral nervous system promotes REM-related apnea genesis in rats. These findings further suggest that endogenous 5-HT, acting at least at peripheral 5-HT3 receptors, may play a baseline physiologic role in the expression of spontaneous central apneas in rats.

Key Words: central apneas • 5-HT • 5-HT3 receptor antagonist • rats • REM sleep


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In anesthetized animals of several species, administration of serotonin (5-HT) or 5-HT analogs produces variable respiratory responses.1 2 3 4 5 6 7 8 9 10 11 12 In freely moving rats, we have shown previously that intraperitoneal administration of 1 mg/kg GR38032F, a selective 5-HT3 receptor antagonist, suppressed spontaneous central apneas, a well-documented behavior in rats.13 14 15 16 17 18 19 20 21 22 23 This effect was especially prominent in rapid eye movement (REM) sleep, during which apneas were completely abolished for at least 4 h following injection. The apnea suppressant effect of GR38032F was paralleled by increased respiratory drive, but BP and heart rate changes were absent at the dose tested.

Suppression of spontaneous apneas during natural sleep by GR38032F is consistent with studies of anesthetized rats in which 5-HT and 2-methyl-5-HT, a selective 5-HT3 receptor agonist, provoked central apneas that were antagonized by GR38032F.10 Since 5-HT does not penetrate the blood-brain barrier (BBB), these results10 indicate that stimulation of peripheral 5-HT3 receptors might have provoked the occurrence of central apneas. In view of that study, performed in anesthetized animals, as well as our previous study in freely moving rats,23 we reasoned that increased serotonergic activity at peripheral 5-HT3 receptors may promote spontaneous sleep-related central apneas. To test this hypothesis, we made intraperitoneal injections of 5-HT and GR38032F to freely moving rats.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Ten adult male Sprague-Dawley rats (300 g) were maintained on a 12-h light (8 AM to 8 PM)/12-h-dark (8 PM to 8 AM) cycle for 1 week, housed in individual cages, and given ad libitum access to food and water. Following 1 week of adaptation, animals were subjected to surgical procedures that will be described briefly herein. All procedures and protocols conformed to the Helsinki accords and the policies of the American Physiological Society regarding animal experimentation.

Rats were anesthetized by intraperitoneal injection for the implantation of cortical electrodes for EEG recording, and neck muscle electrodes for electromyogram (EMG) recording, using a mixture of ketamine (80 mg/kg) and xylazine (10 mg/kg). The surface of the skull was exposed and cleaned with a 20% solution of hydrogen peroxide followed by a solution of 95% isopropyl alcohol. A dental preparation of sodium fluoride (Flura-GEL; Saslow Dental; Mt. Prospect, IL) was applied to harden the skull, and it was allowed to remain for 5 min. The fluoride mixture was then removed from the skull above the parietal cortex. A thin layer of cement (Justi; Saslow Dental) was applied to cover the screw heads and surrounding skull to further promote the adhesion of the implant. EMG electrodes consisted of two ball-shaped wires that were inserted into the bilateral neck musculature. All leads were soldered to a miniature connector (39F1401; Newark Electronics; Schaumburg, IL). Lastly, the entire assembly was fixed to the skull with dental cement.

After surgery, animals were allowed a 1-week recovery before being subjected to another surgical procedure for implantation of a radiotelemetry transmitter (TA11-PXT; Data Sciences International; St. Paul, MN) for monitoring aortic BP and heart period (HP), estimated as pulse interval. After rats were anesthetized (as described), the hair from subxiphoid space to the pelvis was removed. The whole area was scrubbed with iodine and rinsed with alcohol and saline solution. A 4- to 6-cm midline abdominal incision was made to allow good visualization of the area from bifurcation of the aorta to the renal arteries. A retractor was used to expose the contents of the abdomen, and the intestine was held back using saline solution-moistened gauze sponges. The aorta was dissected from the surrounding fat and connective tissues using sterile cotton applicators. A 3-0 silk suture was placed beneath the aorta, and traction was applied to the suture to restrict the blood flow. The implant was held by forceps while the aorta was punctured just cranial to the bifurcation using a 21-gauge needle bent at the beveled end. The tip of the catheter was inserted under the needle using the needle as a guide until the thin-walled BP sensor section was within the vessel. Finally, one drop of tissue adhesive (Vetbond; 3M; St. Paul, MN) was applied to the puncture site and covered with a small square of cellulose fiber (approximately 5 mm2) for sealing the puncture after catheter insertion. The radio implant was attached to the abdominal wall by 3-0 silk suture, and the incision was closed in layers.

After the second surgical procedure, animals were allowed a 1-week recovery period before being used in the study. Each rat was recorded on four occasions, with recordings for an individual animal separated by at least 3 days. Fifteen minutes before recording, each animal received, in random order, one of the following: (1) saline solution (control); (2) 0.79 mg/kg 5-HT; (3) 0.1 mg/kg GR38032F plus 0.79 mg/kg 5-HT; or (4) 0.1 mg/kg GR38032F. For the GR38032F plus 5-HT condition, 0.1 mg/kg GR38032F was administered at 9:30 AM, followed by 0.79 mg/kg 5-HT at 9:45 AM. Polygraphic recordings were made from 10 AM to 4 PM.

Respiration was recorded by placing each rat, unrestrained, inside a single-chamber plethysmograph (PLYUNIR/U; Buxco Electronics; Sharon, CT) (dimension 6 inches wide x 10 inches long x 6 inches high) ventilated with a bias flow of fresh air at a rate of 2 L/min. A cable plugged onto the animal's connector and passed through a sealed port carried the bioelectrical activity from the head. Respiration, BP, EEG, and EMG were displayed on a video monitor and simultaneously digitized 500 times per second and stored on computer disk (Experimenter's Workbench; Datawave Technologies; Longmont, CO). Sleep and waking states were assessed using the biparietal EEG and nuchal EMG signals on 10-s epochs as described by Benington and coworkers.24 This software discriminated wakefulness as a high-frequency, low-amplitude EEG with a concomitant high EMG tone; non-REM (NREM) sleep by increased spindle and theta activity together with decreased EMG tone; and REM sleep by a low ratio of a delta-to-theta activity and an absence of EMG tone.

As in previous investigations,15 16 19 20 21 22 23 sleep apneas, defined as cessation of respiratory effort for at least 2.5 s, were scored for each recording session and were associated with the stage in which they occurred: NREM or REM sleep. The duration requirement of 2.5 s represents at least two "missed" breaths, which is analogous to a 10-s apnea duration requirement in humans. The events detected represent central apneas, because decreased ventilation associated with obstructed or occluded airways would generate an increased plethysmographic signal, rather than a pause. As in previous reports, apneas were observed to occur as pauses between breaths (spontaneous apneas) or immediately following a sigh (postsigh [PS] apneas). Also as in previous reports, sighs were identified as tidal volumes at least 150% greater than the mean tidal volume for each recording.16 Apnea index, defined as apneas per hour in a stage, were separately determined for NREM and REM sleep.

The timing and volume of each breath were scored by automatic analysis (Experimenter's Workbench; Datawave Technologies). For each animal, the mean respiratory rate (RR) and inspiratory minute ventilation (E) was computed for wakefulness throughout the 6-h control recording and used as a baseline to normalize respiration during sleep and during administration of drugs in that animal. Similar software was employed to analyze the BP waveform; for each beat of each recording, systolic BP, diastolic BP, and pulse interval were measured. The pulse interval provided a beat-by-beat estimate of HP. Mean BP was estimated according to the weighted average of systolic BP and diastolic BP for each beat: mean BP = diastolic BP + (systolic BP - diastolic BP)/3. The parameters for each beat were also classified according to the sleep-wake state and recording hour during which they occurred.

The effects of sleep stage (NREM vs REM) and injection (control vs three active injections) on apnea indexes, respiratory pattern, BP, and HP were tested using analysis of variance (ANOVA) with repeated measures. Multiple comparisons were controlled using Fisher's protected least-significance difference. One-way ANOVA was also performed by nonparametric (Kruskal-Wallis) analysis. Conclusions using parametric and nonparametric ANOVA were identical in all cases.


   Results
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 Abstract
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 Materials and Methods
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Discussion
 References
 
Figure 1 shows the effects of 5-HT (0.79 mg/kg), GR38032F (0.1 mg/kg) plus 5-HT (0.79 mg/kg), and GR38032F (0.1 mg/kg) on spontaneous apneas in NREM sleep during the 6 h of polygraphic recording. During NREM sleep, spontaneous apnea index was not affected by any drug treatment (p = 0.97).



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  		Figure 1. The effect of 5-HT (0.79 mg/kg), GR38032F (0.1 mg/kg) plus 5-HT (0.79 mg/kg), and GR38032F (0.1 mg/kg) on spontaneous apneas in NREM sleep. Spontaneous apnea index was not affected by any drug treatment (p = 0.97).

 
The effects of 5-HT (0.79 mg/kg), GR38032 (0.1 mg/kg) plus 5-HT (0.79 mg/kg), and GR38032F (0.1 mg/kg) on spontaneous apneas during REM sleep are shown in Figure 2 . Spontaneous apnea expression significantly increased following 5-HT treatment when compared with control recording (> 250% increase; p = 0.01), but this increase was abolished by pretreatment with GR38032F (p = 0.05 vs 5-HT alone; p = 0.99 vs control). Administration of GR38032F alone had no effect on REM sleep spontaneous apneas (p = 0.51).



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  		Figure 2. Effects of 5-HT (0.79 mg/kg), GR38032F (0.1 mg/kg) plus 5-HT (0.79 mg/kg), and GR38032F (0.1 mg/kg) on spontaneous apneas during REM sleep. Spontaneous apnea expression increased following 5-HT treatment (> 250% increase; p = 0.01), but the increase was abolished by pretreatment with GR38032F (p = 0.05 vs 5-HT alone; p = 0.99 vs control). GR38032F had no effect on spontaneous apneas (p = 0.51).

 
Percentages of waking, NREM, and REM sleep during 6 h of polygraphic recording following intraperitoneal administration of 5-HT and GR38032F to rats are shown in Table 1 . Sleep architecture was not affected by any drug treatment (p > 0.4 for each).


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  		Table 1. Effects of 5-HT and GR38032F on Sleep/Wake Architecture*

 
No condition tested had a significant effect on RR, E, mean BP, HP, or PS apnea index (data not shown).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study shows for the first time (to our knowledge) that manipulation of peripheral serotonin receptors can exert a potent influence on the generation of central apneas during REM sleep in rats. Specifically, the present results confirm our hypothesis that systemic administration of 5-HT would increase spontaneous apnea expression in sleep. Although the dose of 5-HT employed had no effect on sleep, cardiovascular variables, RR, or E, the REM-related spontaneous apnea index increased > 250%. Because NREM apneas were unaffected, we further conclude that the mechanisms of apnea genesis are at least partially sleep-state specific.

These and previous23 findings demonstrate that exogenous administration of 5-HT3 agonists and antagonists at various doses produces changes in apnea expression that are specific to REM sleep. These findings, taken together, argue very strongly that there is a physiologic role for endogenous serotonergic activity in modulating the expression of apnea during REM sleep. Moreover, because 5-HT does not cross the BBB, the finding that 5-HT exerts a converse effect to GR38032F argues that the relevant receptors are located in the peripheral nervous system. Further, the present data suggest that the action of supraphysiologic levels of 5-HT on apneas is receptor mediated. Pretreatment with a low dose (0.1 mg/kg) of GR38032F, which had no independent effect on any measured parameter, including apneas, fully blocked the effects of exogenous 5-HT on apnea expression.

The location of these receptors cannot be identified from the present data. Still, the nodose ganglia represent a likely site that may account for the observed apnea-promoting effects of serotonin. Several studies have concluded that the apnea component of the Bezold-Jarisch reflex results from the action of serotonin at the nodose ganglia in cats6 25 26 and rats.10 27 IV administration of 5-HT or 5-HT3 agonists also stimulates pulmonary vagal receptors,27 which may contribute significantly to the apneic response. However, our finding that 5-HT administration had no impact on PS apneas suggests that the operation of pulmonary stretch receptors was not grossly altered.

Although species differences may be substantial,5 several studies in rat demonstrate that, in addition to its impact on vagal signaling, 5-HT also elicits increased firing from carotid body chemoreceptors27 28 29 30 and increased E.27 28 Although chemoreceptor-mediated effects on apnea cannot be ruled out, the data of McQueen et al27 strongly suggest that IV 5-HT elicits apnea via a vagal pathway, while the chemoreceptor activation opposes apnea genesis in the anesthetized rat.

The 5-HT-induced Bezold-Jarisch reflex in anesthetized animals includes apnea and bradycardia. At the dose employed, 5-HT did not elicit changes in either heart rate or mean BP over the 6-h recording period. Beat-to-beat heart rate and BP variability, assessed as coefficients of variation, were also unaffected by 5-HT at the dose tested. The observed dissociation of cardiovascular and respiratory responses to 5-HT argues that changes in apnea expression were not baroreceptor mediated.

Although the Bezold-Jarisch reflex in anesthetized animals and 5-HT-induced apneas in REM sleep are not the same phenomenon, they may be related by similar mechanisms. When 5-HT receptors are strongly manipulated by exogenous means, ie, either with serotonergic agonists or antagonists, the expression of spontaneous apneas in REM sleep can be amplified or suppressed. However, our observation that 1 mg/kg GR38032F significantly suppressed REM apneas23 does not preclude a role for 5-HT2 or other 5-HT receptor subtypes in the peripheral regulation of the apnea expression.

We15 16 22 and others13 14 17 18 have demonstrated in rats that apnea frequency increases from deep slow-wave sleep to light NREM sleep to REM sleep, as is the case in man.31 The high incidence of apnea expression during REM sleep may be related to respiratory changes that take place during this sleep state. Typically, during REM sleep, breathing becomes shallow and irregular32 33 34 35 36 and E is at its lowest point.37 This background of low respiratory output coupled with strong phasic changes in autonomic activity38 may render respiratory homeostasis during REM sleep more vulnerable to interruption by apnea. The role of 5-HT activity in the peripheral nervous system in REM apnea genesis may arise from a serotonergic modulation of either tonic or phasic respiratory afferent activity, especially in the vagus nerves. The brainstem respiratory integrating areas may be rendered more vulnerable to fluctuating afferent inputs during REM sleep. The present data, however, do not allow identification of the mechanisms underlying the serotonergic influence on apnea genesis.

In conclusion, we found that the exacerbation of spontaneous apnea during REM sleep produced by peripherally administered 5-HT is receptor mediated in rats. These findings also suggest a possible physiologic role for endogenous 5-HT in the peripheral nervous system in modulating sleep apnea expression under baseline conditions.


   Footnotes
 
Abbreviations: ANOVA = analysis of variance; BBB = blood-brain barrier; EMG = electromyogram; HP = heart period; 5-HT = serotonin; NREM = nonrapid eye movement sleep; PS = postsigh; REM = rapid eye movement sleep; RR = respiratory rate; E = minute ventilation

Received for publication July 10, 1998. Accepted for publication November 16, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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