SEROTONIN 1A RECEPTOR & METABOLIC IMAGING IN DEPRESSION

血清素 1A 受体

• 批准号: 6499289
• 负责人: DAVID J KUPFER
• 金额: $ 31.59万
• 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: 1999-05-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499289
• 关键词: amygdala; antidepressants; bioimaging /biomedical imaging; brain circulation; brain imaging /visualization /scanning; carbon; clinical research; cortisol; fluorine; glucose metabolism; human subject; major depression; mental disorder chemotherapy; neuroanatomy; neuropharmacology; positron emission tomography; prefrontal lobe /cortex; radionuclide imaging /scanning; radionuclides; radiotracer; receptor binding; receptor expression; serotonin receptor; sertraline; temporal lobe /cortex

DESCRIPTION: (Applicant's abstract) Multiple lines of evidence suggest that serotonin1A (5HT1A) receptor function is abnormal in major depressive disorder (MDD) and that somatic antidepressant therapies effect changes in 5HT1A receptor function that are relevant to treatment efficacy. The data supporting these hypotheses have been obtained by assessing neuroendocrine and temperature responses to 5HT1A agonists in MDD subjects, measuring 5HT1A receptor binding in brain tissue acquired post mortem from small samples of MDD subjects, and examining changes in 5HT1A receptor binding in rats following antidepressant drug (AD) administration. However, there has been no direct demonstration of a central 5HT1A receptor abnormality or an effect of antidepressant treatment on 5HT1A receptor pharmacology in living depressed subjects. The development of a highly selective 5-HT1A receptor radioligand for positron emission tomography (PET) imaging, [carbonyl-11C]- WAY-100635, has recently made direct, noninvasive exploration of the central 5HT1A receptor binding potential (BP) possible in MDD. To advance knowledge regarding the neurobiology of MDD and the mechanisms of AD treatment, PET and [carbonyl-11C]WAY-100635 will be used to compare the 5HT1A receptor BP between MDD and healthy control subjects and between the pre-and post-treatment conditions in the MDD subjects. Images of 18F-fluorodeoxyglucose (FDG) uptake will be acquired in the same scan session to evaluate the relationship between regional 5HT1A receptor BP and the glucose metabolic abnormalities previously identified in MDD. Endocrine assessments of cortisol secret-ion are also examined prior to imaging to determine whether down-regulation of hippocampal 5HT1A receptors occurs in response to the hypercortisolism associated with MDD as it does in experimental animals during stress and glucocorticoid administration. The imaging and endocrine measures are repeated following an 8 week interval during which the depressives are treated with the antidepressant drug sertraline. Pilot imaging data suggest that the differences in the 5HT1A receptor BP between unmedicated depressives and controls are robust in the mesiotemporal cortex and the ventrolateral and ventromedial prefrontal cortex (PFC). If a link between reduced 5HT1A receptor BP in the mesiotemporal cortex (which includes the hippocampus) and abnormal cortisol secretion is established in MDD, then normalization of this abnormality during treatment may have prognostic implications. In the ventrolateral and ventromedial PFC, the magnitude of the abnormal reductions of 5HT1A receptor BP were proportionately larger than the abnormalities of metabolism and grey matter volume previously shown in these areas in MDD, suggesting the 5HT1A receptor imaging measures may provide sensitive markers of pathology that can guide future post mortem histological and histochemical studies of MDD.

描述：（申请人的摘要）多种证据表明，重度抑郁症（MDD）中血清素1A（5HT1A）受体功能异常，并且躯体抗抑郁疗法会影响与治疗效果相关的5HT1A受体功能的变化。支持这些假设的数据是通过评估 MDD 受试者对 5HT1A 激动剂的神经内分泌和温度反应、测量 MDD 受试者死后小样本脑组织中 5HT1A 受体结合以及检查大鼠服用抗抑郁药物后 5HT1A 受体结合的变化而获得的。 （AD）管理。然而，尚无直接证据表明中枢 5HT1A 受体异常或抗抑郁治疗对活着的抑郁受试者中 5HT1A 受体药理学的影响。用于正电子发射断层扫描 (PET) 成像的高选择性 5-HT1A 受体放射性配体 [carbonyl-11C]- WAY-100635 的开发，最近使得在 MDD 中直接、无创地探索中心 5HT1A 受体结合电位 (BP) 成为可能。为了加深对 MDD 神经生物学和 AD 治疗机制的了解，PET 和 [carbonyl-11C]WAY-100635 将用于比较 MDD 和健康对照受试者之间以及治疗前和治疗后条件之间的 5HT1A 受体 BP在 MDD 科目中。将在同一扫描过程中获取 18F-氟脱氧葡萄糖 (FDG) 摄取图像，以评估区域 5HT1A 受体 BP 与先前在 MDD 中发现的葡萄糖代谢异常之间的关系。在成像之前还检查了皮质醇分泌离子的内分泌评估，以确定海马 5HT1A 受体的下调是否是响应与 MDD 相关的皮质醇增多症而发生的，就像实验动物在应激和糖皮质激素给药期间的情况一样。抑郁症患者接受抗抑郁药物舍曲林治疗后，每隔 8 周重复进行影像学和内分泌测量。初步成像数据表明，未接受药物治疗的抑郁症患者与对照组之间的 5HT1A 受体 BP 在颞叶皮质以及腹外侧和腹内侧前额皮质 (PFC) 中存在显着差异。如果在 MDD 中建立了内侧颞叶皮层（包括海马）中 5HT1A 受体血压降低与皮质醇分泌异常之间的联系，那么治疗期间这种异常的正常化可能具有预后意义。在腹外侧和腹内侧 PFC 中，5HT1A 受体 BP 异常降低的幅度按比例大于先前在 MDD 中这些区域显示的代谢和灰质体积异常，表明 5HT1A 受体成像测量可能提供敏感的病理标志物，可以指导未来 MDD 的死后组织学和组织化学研究。

项目成果

Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635.

使用正电子发射断层扫描和 [11C]WAY-100635 测量抗抑郁药物治疗前后抑郁症成人的 5-HT1A 受体结合。

• 发表时间: 2007-07
• 作者: Moses;Price, Julie C;Thase, Michael E;Meltzer, Carolyn Cidis;Kupfer, David J;Mathis, Chester A;Bogers, Wendy D;Berman, Susan R;Houck, Patricia R;Schneider, Trisha N;Drevets, Wayne C
• 通讯作者: Drevets, Wayne C