CEREBRAL 5HT1A RECEPTORS AND METABOLISM IN DEPRESSION

抑郁症中的大脑 5HT1A 受体和代谢

• 批准号: 6185587
• 负责人: WAYNE C DREVETS
• 金额: $ 10.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6185587
• 关键词: baboons; bioimaging /biomedical imaging; clinical research; cortisol; glucose metabolism; hormone regulation /control mechanism; human subject; major depression; positron emission tomography; radiotracer; receptor binding; serotonin receptor

DESCRIPTION (adapted from applicant's abstract): To elucidate the neurobiology of MDD, positron emission tomographic (PET) measures of serotonin~A (5HT1A) receptor binding and glucose metabolism will be compared between depressed and control subjects and between the pre-and post-treatment conditions of major depressive disorder (MDD). Previous studies assessing neuroendocrine and temperature responses to 5HT1A agonists in MDD subjects, measuring 5HT1A receptor density in brain tissue acquired post mortem from small samples of MDD subjects, or examining changes in 5HT1A receptor binding in rats following antidepressant drug (AD) administration suggested that SHT1A receptor function is abnormal in MDD and that AD therapies induce changes in SHT1A receptor function that are relevant to treatment efficacy. However, there has been no direct demonstration of a central SHT1A receptor abnormality or an effect of AD treatment on 5HT1A receptor pharmacology in living depressed subjects. The development of a highly selective 5-HT1A receptor radioligand for PET, [carbonyl 11C]-WAY- 100635, has recently made direct, noninvasive exploration of the central 5HT1A receptor binding potential (BP) possible in MDD. PET images of [carbonyl-11C]-WAY-100635 and 18F-fluorodeoxyglucose (FDG) uptake will be acquired in the same scan session in depressed and healthy controls to evaluate the relationship between regional 5HT1A receptor BP and the glucose metabolic abnormalities previously identified in MDD. Cortisol secretion prior to imaging is also assessed to determine whether the down-regulation of hippocampal 5HT1A receptors seen in rats exposed to repeated stress or exogenous glucocorticoids also results from hypercortisolism associated with MDD. The imaging and endocrine measures are repeated following an 8 week interval during which the depressives are treated with the selective serotonin reuptake inhibitor, citalopram. This project takes the PI's career development in the new direction of neuroreceptor imaging. The training and research plans build upon his previous experience in conducting PET studies of blood flow and metabolism by adding capabilities for determining whether brain regions where physiological abnormalities are found in depression are also characterized by abnormal serotonin receptor pharmacology. The PI will acquire skills for characterizing the in vivo binding characteristics of a novel PET radioligand in humans and baboons, for implementing various tracer kinetic models for the derivation of receptor BP, and for comparing receptor image data between depressed and healthy samples. Training is also received in the application of multivariate statistical approaches and neural network modelling techniques for assessing interrelationships between regional 5HT1A receptor BP, metabolism, and cortisol in multiple interconnected structures.

描述（改编自申请人摘要）：阐明神经生物学 MDD，正电子发射断层扫描（PET）测量5-羟色胺~A（5 HT 1A） 受体结合和葡萄糖代谢将比较抑郁症和 对照受试者和治疗前和治疗后的条件之间的主要 抑郁症（MDD）。以前的研究评估神经内分泌和 MDD受试者对5 HT 1A激动剂的温度反应，测量5 HT 1A 从MDD的小样本死后获得的脑组织中的受体密度 受试者，或检查大鼠中5 HT 1A受体结合的变化， 抗抑郁药（AD）给药提示SHT 1A受体功能 在MDD中是异常的，AD治疗诱导SHT 1A受体的变化 与治疗效果相关的功能。然而，没有 直接证明中枢SHT 1A受体异常或AD效应 治疗5 HT 1A受体药理学在生活抑郁症的主题。 PET用高选择性5-HT 1A受体放射性配体的开发， [羰基11 C]-WAY- 100635，最近进行了直接的非侵入性探索 中枢5 HT 1A受体结合电位（BP）可能在MDD。宠物 [羰基-11 C]-WAY-100635和18 F-氟脱氧葡萄糖（FDG）摄取图像 将在抑郁和健康对照的同一扫描会话中采集， 探讨局部5-HT 1A受体血压与血糖的关系 先前在MDD中发现的代谢异常。皮质醇分泌前 也评估成像以确定是否下调 海马5 HT 1A受体在大鼠暴露于反复应激或 外源性糖皮质激素也可由皮质醇过多引起， MDD。在8周后重复成像和内分泌测量 抑郁症患者接受选择性5-羟色胺治疗的时间间隔 再摄取抑制剂西酞普兰 该项目将PI的职业发展带入新的方向， 神经感受器成像培训和研究计划建立在他以前的基础上。 通过增加PET血流和代谢研究的经验， 能够确定大脑区域的生理功能 抑郁症的特征也是异常的 血清素受体药理学PI将获得表征 新型PET放射性配体在人体内的体内结合特征， 狒狒，用于实施各种示踪动力学模型，用于推导 受体BP，并用于比较抑郁症和抑郁症之间的受体图像数据， 健康的样品。培训还收到在应用多元 用于评估的统计方法和神经网络建模技术 局部5 HT 1A受体血压、代谢和皮质醇之间的相互关系 多个相互连接的结构。