EXCITATORY AMINO ACIDS AND RESPIRATORY FUNCTION

我们在下一个资助期的目标是集中精力 中枢兴奋性氨基酸(EaAs)在调控中的重要作用 呼吸的感觉。这一目标将通过以下方式实现：(1)确定 药物干预中枢神经系统EAA的呼吸效应 全身给药阻断NMDA的神经传递 受体，阻断甘氨酸位点的NMDA受体，阻断非NMDA 受体，阻断谷氨酸的释放；(2)确定中枢神经系统的位置 系统给药的EAA拮抗剂作用于 干扰呼吸活动；以及(3)研究EAA的作用 拮抗剂和其他改变EAA神经传递的药物 肌束腹外侧亚核内的单个神经元 孤立子(VLNTS.将用于以下方面的实验方法 这些研究包括监测去大脑动物的膈神经活动， 在给药期间切断迷走神经，并使动物瘫痪； 将药物微量注射到特定的大脑部位，特别是在大脑的 VLNTS同时监测膈神经活动；损毁VLNTS和 在此基础上评价静脉给药对膈神经的影响 活体VLNTS神经元的单位记录及注意其作用 药物离子附着在这些神经元上；使用整个细胞贴片- 体外脑片中单个VLNTS神经元的钳制记录 制备(大鼠)研究EaS的作用。另外，我们的计划是 使用涉及特异性抗体的免疫组织化学技术 EAA受体亚型以阐明存在哪些EAA受体 呼吸(吸气)神经元。从这些研究中获得的数据 应提供有关CNS EaaS在控制中的作用的新信息 呼吸。我们的数据还应该提供关于中枢神经系统如何 调节呼吸活动。最后，我们的发现将会取得进展 使用EAA拮抗剂治疗中枢神经系统的安全性研究现状 疾病，并可能为预防潜在的有害物质提供基础 这些药物对呼吸系统的影响。

Our goal during the next funding period is to concentrate on the important role that CNS excitatory amino acids (EAAs) have in the control of breathing. This goal will be pursued by: (1) determining the respiratory effects of pharmacologically interfering with CNS EAA neurotransmission by systemic administration of drugs that block NMDA receptors, block the glycine-site NMDA receptor, block non-NMDA receptors, and block the release of glutamate; (2) determine the CNS site of action whereby systemically administered EAA antagonists act to disrupt respiratory activity; and (3) study the effect of EAA antagonists, and other drugs that alter EAA neurotransmission on individual neurons within the ventrolateral subnucleus of the tractus solitarius (VLNTS. The experimental approaches that will be used for these studies include monitoring phrenic nerve activity in decerebrate, vagotomized, and paralyzed animals during drug administration; microinjecting drugs into specific brain sites, particularly into the VLNTS while monitoring phrenic nerve activity; lesioning the VLNTS and evaluating IV administered drugs for phrenic nerve effects under this condition; unit recording of VLNTS neurons in vivo and noting effects of drugs iontopheresed onto these neurons; and using the whole cell patch- clamp recording of single VLNTS neurons in the in vitro brain slice preparation (rat) to study the role of EAAs. In addition, our plan is to use immunohistochemical techniques involving antibodies to specific subtypes of EAA receptors to elucidate which EAA receptors are present on respiratory (inspiratory) neurons. Data obtained from these studies should provide new information on the role of CNS EAAs in controlling breathing. Our data should also provide new insights on how the CNS regulates respiratory activity. Finally, our findings will advance current knowledge on the safety of using EAA antagonists to treat CNS disorders, and may provide a basis for preventing potential deleterious effects of these agents on the respiratory system.