CEREBRAL 5HT1A RECEPTORS AND METABOLISM IN DEPRESSION

描述(摘自申请者的摘要)：阐明神经生物学 MDD患者5-羟色胺~A(5HT1A)的正电子发射断层扫描(PET)测量 抑郁症患者和抑郁症患者的受体结合和葡萄糖代谢情况进行比较。 对照受试者及主治者治疗前后情况 抑郁障碍(MDD)。先前的研究评估神经内分泌和 MDD受试者对5HT1A激动剂的温度反应，测量5HT1A MDD小样本死后获取脑组织的受体密度 受试者，或检测以下大鼠5HT1A受体结合的变化 抗抑郁药(AD)给药提示SHT1a受体功能 在MDD中异常，AD治疗导致SHT1A受体变化 与治疗效果相关的功能。然而，目前还没有 中枢SHT1a受体异常或AD效应的直接证明 活动性抑郁症患者5HT1a受体的药理学治疗。 用于PET的高选择性5-HT1a受体放射配基的研制 [羰基11C]-Way-100635，最近进行了直接的非侵入性勘探 在MDD中可能存在中枢5HT1a受体结合潜力(BP)。宠物 ~(11)C-Way-100635和~(18)F-脱氧葡萄糖摄取的图像 将在抑郁症和健康对照组的同一扫描过程中获得 5HT1a受体区段BP与血糖关系的研究 以前在MDD中发现的代谢异常。皮质醇分泌前期 还评估了对成像的影响，以确定是否下调 反复应激或应激大鼠海马区5HT1a受体 外源性糖皮质激素也是与以下相关的皮质醇增多症的结果 MDD。在8周后重复进行成像和内分泌测量。 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的职业发展带向了新的方向 神经感受器成像。培训和研究计划建立在他之前的基础上 应用正电子发射计算机断层扫描对血流和代谢进行研究的体会 确定大脑区域是否具有生理性的能力 在抑郁症中发现异常也是异常的特征 血清素受体药理学。PI将获得刻画角色的技能 一种新型的PET放射性配基在人体内的结合特性 用于实现各种示踪剂动力学模型以推导出 受体BP，并用于比较抑郁和抑郁之间的受体图像数据 健康的样本。还接受了多变量应用方面的培训 用于评估的统计方法和神经网络建模技术 区域5HT1a受体BP、代谢和皮质醇的相互关系 在多个相互连接的结构中。

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.