CCK MODULATION OF ANXIETY AND THE HPA AXIS

CCK 调节焦虑和 HPA 轴

• 批准号: 2252599
• 负责人: James L Abelson
• 金额: $ 8.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2252599
• 关键词: adrenocorticotropic hormone; cholecystokinin; clinical anxiety; cortisol; hormone receptor; hormone regulation /control mechanism; human subject; hypothalamic pituitary axis; neuroendocrine system; neuropeptide receptor; panic disorder; psychopharmacologic agent; psychopharmacology; stimulant /agonist

Cholecystokinin (CCK) is the most abundant peptide neurotransmitter in the brain and its known distribution, interactions, and functions make it of great interest to psychiatry, but it has been little studied in humans. CCK may play a pathophysiological role in panic disorder--which is a common, disabling disorder with high social morbidity costs. It may also play a role in modulating the hypothalamic-pituitary-adrenal (HPA) axis-- which appears dysregulated in panic, as well as depression and other psychiatric disorders. Agonists of a central CCK receptor (CCK-B) induce panic attacks and activate the HPA axis, but mediating mechanisms have not been identified. The goals of this project are: (l) to further develop the CCK-B agonist pentagastrin as a neuroendocrine probe for studying CCK-B receptor function in humans; (2) to determine whether CCK plays a physiological role in the regulation of the human HPA axis and explore mediating mechanisms; (3) to further develop pentagastrin as a laboratory model of panic disorder and explore its mechanisms of angiogenesis. Five experiments are planned. The first will determine the dose-response curves for HPA activation and subjective symptoms in response to intravenous pentagastrin. The second will examine HPA responses to pentagastrin at different times of day and different levels of basal glucocorticoid activity. The third will test the ability of a selective CCK-B antagonist (CI-988) to block HPA and symptom responses to pentagastrin. The fourth will use metyrapone pre-treatment to examine the effect of reduced cortisol levels on the HPA response to pentagastrin. The fifth will compare panic patients to controls in symptom and HPA responses to pentagastrin and determine whether a cognitive intervention that should reduce the intensity of symptom responses will also reduce the HPA response. Additional experiments will examine adrenergic or GABAergic blockade of pentagastrin effects. If the HPA response to pentagastrin is dose-dependent and independent of symptoms, this will suggest that CCK plays a physiological role in modulating the human HPA axis. If the HPA response is independent of cortisol feedback inhibition, this will differentiate CCK from other stress axis modulators and enhance its value as a new probe for studying HPA axis regulation. If cognitive intervention blocks pentagastrin-induced panic in patients, but the HPA response remains robust and normal, this will contradict the hypothesis that altered CCK-B receptor sensitivity plays a role in the reported panicogenic activity of CCK-B agonists. These studies will build the foundation needed to develop pentagastrin into a widely useful tool for studying neuroendocrine regulatory mechanisms, human CCK-B receptor function, and the pathophysiology of anxiety and affective disorders.

胆囊动蛋白（CCK）是最丰富的肽神经递质 大脑及其已知的分布，相互作用和功能使它成为 精神病学极大的兴趣，但在人类中很少研究。 CCK可能在恐慌症中起病理生理的作用，这是 常见的，残疾疾病，社会发病成本高。它也可能 在调节下丘脑 - 垂体 - 肾上腺（HPA）轴上发挥作用 - 在恐慌以及抑郁症和其他 精神疾病。中央CCK受体（CCK-B）的激动剂诱导 恐慌发作并激活HPA轴，但介导机制却没有 已确定。该项目的目标是：（l）进一步发展 CCK-B激动剂五核酸酯作为研究CCK-B的神经内分泌探针 人类的受体功能； （2）确定CCK是否扮演 在人体HPA轴调节中的生理作用并探索 中介机制； （3）进一步发展为实验室 恐慌症模型并探索其血管生成机制。 计划了五个实验。第一个将确定剂量反应 HPA激活和主观症状的曲线响应 静脉注射五藻。第二个将检查HPA对 在一天中的不同时间和不同水平的基础上 糖皮质激素活性。第三个将测试选择性的能力 CCK-B拮抗剂（CI-988）阻止HPA和症状反应 pentagastrin。第四将使用Metyrapone预处理检查 皮质醇水平降低对HPA对戊酸戊酸酯反应的影响。这 第五将比较恐慌患者与症状和HPA反应的对照 要五牙肌并确定是否应进行认知干预措施 降低症状反应的强度也将减少HPA 回复。其他实验将检查肾上腺素能或GABA能 五角肌效应的封锁。 如果HPA对五牙糖蛋白的响应是剂量依赖性的，并且独立于 症状，这表明CCK在 调节人HPA轴。如果HPA响应独立于 皮质醇反馈抑制，这将使CCK与其他CCK区分开 应力轴调节器，并提高其作为研究的新探测器的价值 HPA轴调节。如果认知干预会阻止五牙糖引起的 患者的恐慌，但HPA反应保持稳健和正常，这是 将与改变CCK-B受体灵敏度的假设相矛盾 在报道的CCK-B激动剂的合理活性中起作用。这些 研究将建立开发五牙糖的基础 广泛有用的工具用于研究神经内分泌调节机制， 人CCK-B受体功能，以及焦虑和 情感障碍。