PHARMACOLOGY OF SLEEP APNEA

大量证据表明，5-羟色胺能(5- 睡眠时上呼吸道运动神经元的兴奋性输入在睡眠中起作用 在抑制它们的活动从而允许呼吸道通畅中起主要作用 结案了。如果是这样，那么操纵5-羟色胺系统来忍受 睡眠期间这些运动神经元的5-羟色胺水平维持和/或使用 选择性的5-羟色胺激动剂兴奋这些运动神经元，可以提供 阻塞性睡眠呼吸暂停的药物治疗。这一概念是 这项提议。支持证据来自最近的研究，使用我们的 阻塞性睡眠呼吸暂停动物模型，英国斗牛犬。我们 系统地给予曲唑酮和L-色氨酸的组合， 认为可以提高5-羟色胺水平，并在这些部位提供激动剂活性 运动神经元。这种疗法在一定程度上减少了睡眠-呼吸障碍- 依附时尚。然而，所需曲唑酮的剂量更高。 比目前在人类身上使用的更多。5-羟色胺的进一步发展 药物治疗需要了解特定的5-羟色胺受体亚型 参与兴奋性效应的运动神经元选择选择性 激动剂。此外，不同策略对 上呼吸道运动神经元5-羟色胺水平升高需要确定。 对于这两种方法中的每一种都可以增加5-羟色胺的激发 睡眠中的上呼吸道运动神经元，我们会追求互补 在两个动物模型上进行研究。麻醉大鼠将在特定情况下使用 目标1直接向舌下(XII)运动进行微量注射研究 神经元阐明介导兴奋的特异性5-羟色胺受体 使用药理探针；并针对特定目标3检查效果 不同的5-羟色胺增强剂对XII激活的影响。这些研究提供了 关于正常哺乳动物的药理学的基本信息。英国人 斗牛犬将被用来记录，在这种患有先天性疾病的动物中 气道狭窄，针对特定5-羟色胺受体的拮抗剂抑制 清醒时的气道扩张肌肉活动和引起的气道塌陷 (具体目标2)，以及增加5-羟色胺的药物是否能缓解睡眠- 呼吸紊乱(具体目标4)。因此，这些项目旨在 具体阐述5-羟色胺作用的基本药理机制 在控制上呼吸道运动神经元活动方面，但具有实用性 为这一常见疾病开发药物疗法的目标。

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.