PHARMACOLOGY OF SLEEP APNEA

相当多的证据表明，减少肾上腺素能（5- HT）兴奋性输入在睡眠中对上气道运动神经元起着重要作用。 主要作用是抑制其活动，从而使气道 结束如果是这样的话，那么操纵5-HT系统来忍受 在睡眠期间维持这些运动神经元的5-HT水平，和/或使用 选择性5-羟色胺激动剂，以兴奋这些运动神经元，可以提供一个 阻塞性睡眠呼吸暂停综合征的治疗这一概念是 这个提议。支持证据来自最近的研究， 阻塞性睡眠呼吸暂停的动物模型，英国斗牛犬。我们 系统地给予曲唑酮和L-色氨酸的组合， 被认为增加5-HT水平，并在这些水平提供激动剂活性， 运动神经元这种治疗减少了睡眠呼吸障碍的剂量- 依赖的方式。然而，曲唑酮所需的剂量更高， 比目前在人类身上使用的要多。5-HT的进一步开发 药物治疗需要了解特定的5-HT受体亚型 参与运动神经元选择性兴奋效应 激动剂此外，不同策略的相对功效， 需要确定上气道运动神经元5-HT水平增加。 对于这两种方法中的每一种，以增加5-HT的兴奋， 上呼吸道运动神经元在睡眠中，我们将追求互补 两种动物模型的研究。麻醉大鼠将用于特定的 目的1直接显微注射研究舌下神经（XII）运动 神经元，以阐明特定的5-HT受体介导的兴奋 使用药理学探针;在具体目标3中， 不同的5-HT增强药物对XII激活的影响。这些研究提供 关于正常哺乳动物药理学的基本信息。英语 斗牛犬将用于记录在该动物中是否存在先天性 气道狭窄，针对特定5-HT受体的拮抗剂抑制 气道扩张肌肉活动，并在清醒时导致气道塌陷 （具体目标2），以及增加5-HT的药物是否缓解睡眠- 呼吸紊乱（具体目标4）。因此，这些项目旨在 具体说明5-HT作用的基本药理学机制 在控制上气道运动神经元活动，但与实际 目的是为这种常见的疾病开发一种药物疗法。

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.