Serotonin
Culprit or Promising Therapy for Obstructive Sleep Apnea?

Sigrid Carlen Veasey

Sleep Medicine Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

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As our concern for significant cardiovascular and neurobehavioral morbidity from obstructive sleep apnea-hypopnea syndrome (OSAHS) continues to mount, so does the need for safe, well-tolerated, and effective pharmacotherapeutics for this prevalent disorder. Serotonin (5-HT) has been prominently featured in the quest for a pharmacotherapeutic for sleep apnea. Presently, however, 5-HT is being pulled in opposite directions along this quest, implicated as both a contributor to sleep apnea (1) and as a promising therapy for the disease (4). Indeed, clinical trials are presently testing the efficacy of both serotoninergic agonists and antagonists in treating persons with obstructive sleep-disordered breathing. Which is the right direction for serotonin, or could both directions be correct? In this month's Journal (pp. 1191-1197) Nakano and colleagues take a careful step back to better delineate the role serotonin plays in the pathogenesis of obstructive sleep-disordered breathing (9). This is accomplished through their more complete characterization of a promising animal model of the disorder and comparison with control animals. The purpose of this editorial is to discuss this new animal model (the obese Zucker rat) for sleep apnea, and then to use the data of Nakano and colleagues to make better sense of the seemingly contradictory findings in past studies concerning 5-HT and sleep-disordered breathing.

The pathogenesis of obstructive sleep-disordered breathing (OSDB), along the entire spectrum from upper airway resistance syndrome to obstructive sleep apnea, involves two components (10, 11). First, the upper airway is either narrow or more collapsible, so that upper airway dilator muscle activity is requisite for airway patency. Second, sleep-dependent alterations in dilator activity result in OSDB events. How applicable is the obese Zucker rat as a model of OSDB? The model has not been rigorously tested for sleep-dependent apneas, hypopneas, or respiratory effort-related arousals. Nevertheless, the rats do have narrowed upper airways (12), and in this article, Nakano and colleagues describe a more collapsible upper airway in the obese Zucker rats than in lean littermates (9). Further, this study finds that a ritanserin-induced reduction in upper airway dilator muscle activity in the obese Zucker rat is associated with increased pharyngeal collapsibility, reduced ventilation, and an increase in oxygen consumption. The increased oxygen consumption at rest, and without body temperature change, is consistent with an increase in the work of breathing, which may in part be explained by increased upper airway resistance. With these novel observations, the obese Zucker rat is an excellent model of enhanced upper airway collapsibility, and reliance on upper airway dilator activity for patency and maintenance of ventilation. The key component missing is sleep-related changes in muscle activity causing obstructive sleep-disordered breathing. Although this characterization is desired, without this phenotype, the model is still of considerable value. Characterizing obstructive sleep-disordered breathing, particularly if events are subtle, may take substantial time. As a rat model, the obese Zucker provides a strain in which detailed neurochemical, neuroanatomical, and molecular studies can be performed to provide further insight into the mechanisms of upper airway collapse, how an animal adapts to a compromised upper airway, and the mechanisms of disease progression. This is a model with substantial promise in our quest for a drug therapy for sleep apnea that augments upper airway motor activity.

The data in the study of Nakano and coworkers (9) provide insight into controversies concerning the influences that 5-HT has on respiration. One controversy has evolved around the 5-HT antagonist used in this study, that is, ritanserin, which is an antagonist at 5-HT_2A, 5-HT_2C, and 5-HT₇ receptors. Administration of ritanserin in the English bulldog model of OSDB causes decreased activity of upper airway dilator muscles, more so than the diaphragm, with concurrent oxyhemoglobin desaturations and collapse of the upper airway (13). In contrast, ritanserin administered in similar doses to normally respiring rats results in increased phrenic and hypoglossal activity (1). The data from Nakano and coworkers (9) show that these different results are not simply explained by species differences. In their study, Nakano and colleagues found that ritanserin did not alter ventilation in adult lean Zucker rats, but in the adult obese Zucker rats produced reductions in upper airway dilator activity, increased collapsibility of the upper airway, decreased ventilation, and increased oxygen consumption at rest, a finding compatible with previous results in the bulldog (13). Thus, the effect of ritanserin seems to depend on the status of the upper airway. It causes upper airway collapse in those animals with pre-existing compromise of the upper airwaythe adult obese Zucker rat and the English bulldog. This may reflect 5-HT involvement in the neuronal adaptation mechanisms for a narrowed upper airway, as in observed in other situations. For example, long-term facilitation of respiratory motor output after exposure to intermittent hypoxia is 5-HT dependent (14). Further spinal plasticity elicited by cervical dorsal rhizotomy augments the response to 5-HT antagonism (15).

A second issue with respect to 5-HT and sleep apnea relates to the complex pharmacology of 5-HT receptors. There are at least 14 5-HT receptor subtypes in most mammals, distinguished molecularly and pharmacologically. In contrast to the effects of ritanserin, ondansetron, a 5-HT₃ antagonist, reduces rapid eye movement (REM) sleep-disordered breathing events in the English bulldog (16). Increased respiratory drive is also seen in the normal rat, where ondansetron increases hypoglossal activity in the anesthetized rat (17) and reduces central sleep apneic events during REM sleep (2). This effect is not likely to be mediated by direct effects on hypoglossal motoneurons because microinjection of ondansetron in the hypoglossal nucleus in rats has no effect on hypoglossal activity (17). Rather, this effect is likely peripheral, occurring at the nodose ganglion (3).

Faced with this degree of complexity, that is, different receptor subtypes for 5-HT, differences between animals with and without upper airway compromise, we are not yet able to adequately answer the question, "Which approach for OSAHS pharmacotherapeutical development is optimal, then, 5-HT agonists or antagonists?" Nakano and colleagues have taken an important step in developing an animal model to provide further insight (9). Their work would argue that we need to use animals with longstanding narrowing of the upper airway if we are to advance our understanding of the pharmacology of upper airway control so that it is relevant to sleep apnea. Moreover, this rodent model, where the site of action and 5-HT receptor subtypes can be determined, allows the study of whether and how upper airway narrowing and collapse leads to plasticity in the role of serotonin in upper airway motor control.

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