Considerable evidence suggests that a reduction in the serotoninergic (5- HT) excitatory input to upper airway motoneurons during sleep plays a major role in the depression of their activity thus permitting airway closure. If this is so, then manipulating the 5-HT system to endure the maintenance of 5-HT levels at these motoneurons during sleep, and/or using selective 5-HT agonists to excite these motoneurons, could provide a pharmacotherapy for obstructive sleep apnea. This concept is the basis of this proposal. Supporting evidence comes from recent studies using our animal model of obstructive sleep apnea, the English bulldog. We systematically administered a combination of trazodone and L-tryptophan, thought to increase 5-HT levels and provide agonist activity at these motoneurons. The treatment reduced sleep-disordered breathing in a dose- dependent fashion. However, the doses of trazodone required were higher than those currently employed in humans. Further development of a 5-HT pharmacotherapy requires knowledge of the specific 5-HT receptor subtypes involved in the excitatory effect at the motoneuron to choose selective agonists. Additionally, the relative efficacy of different strategies to increase 5-HT levels at upper airway motoneurons needs to be determined. For each of these two approaches to increase the 5-HT excitation of the upper airway motoneurons during sleep, we will pursue complementary studies in two animal models. Anesthetized rats will be used in Specific Aim 1 for direct microinjection studies into the hypoglossal (XII) motor neurons to elucidate the specific 5-HT receptors mediating excitation using pharmacological probes; and in Specific Aim 3 to examine the effect of different 5-HT-enhancing drugs on XII activation. These studies provide basic information about the pharmacology in a normal mammal. The English bulldog will be used to document whether, in this animal with congenital airway narrowing, antagonists directed at specific 5-HT receptors suppress airway dilating muscle activity and cause airway collapse during waking (Specific Aim 2), and whether drugs that increase 5-HT relieve sleep- disordered breathing (Specific Aim 4). These projects are thus designed to specifically address basic pharmacological mechanisms of the role of 5-HT in controlling upper airway motoneuronal activity, but with the practical goal of developing a pharmacotherapy for this common disorder.
Showing the most recent 10 out of 77 publications
