5HT Function /Rceptor Imaging In Mood/Anxiety Disorders

情绪/焦虑障碍中的 5HT 功能/受体成像

• 批准号: 7136358
• 负责人: WAYNE C DREVETS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7136358
• 关键词: anxiety disorders; behavioral /social science research tag; behavioral genetics; bioimaging /biomedical imaging; brain imaging /visualization /scanning; brain mapping; clinical depression; genetic polymorphism; human subject; hypothalamic pituitary adrenal axis; major depression; mood disorders; neuropharmacology; neuropsychological tests; neuropsychology; panic disorder; patient oriented research; positron emission tomography; postpartum depression; posttraumatic stress disorder; radiotracer; receptor binding; receptor expression; serotonin; serotonin receptor; serotonin transporter

A variety of evidence suggests serotonin 1A (5-HT1A) receptor function is abnormal in panic disorder (PD), postraumatic stress disorder (PTSD), and depression. This protocol investigates the pharmacological basis for 5-HT1A abnormalities in vivo by applying positron emission tomography (PET) and the 5-HT1A receptor radioligand [F-18]FC-WAY100635 to assess 5-HT1A binding potential in panic disorder, postraumatic stress disorder, and unipolar and bipolar depression. Because central 5-HT1A receptor density is down-regulated in rodents by corticosterone administration and by stress-mediated corticosterone secretion, assessments of HPA-axis activity were assessed to determine whether down-regulation of 5-HT1A receptors correlates with cortisol hypersecretion in PD, PTSD, and MDD. PET images of 5-HT1A binding were acquired in subjects who are unmedicated PD, PTSD and depressed patients, or are healthy volunteers. The 5-HT1A receptor volume of distribution was calculated with a two tissue compartment model of PET data after a bolus infusion of ([F-18]FCWAY). The 5-HT1A receptor volume of distribution in the hippocampus, amygdala, ventral ACC, and orbital cortex were compared between the entire depressive and control samples. The relationships between 5-HT1A receptor volume of distribution and salivary cortisol and between 5-HT1A receptor volume of distribution and cerebrospinal fluid concentrations of corticotrophin releasing hormone (CRH), were assessed by linear regression analysis. During the past year, an additional 12 subjects with MDD and 6 with BD entered into this study for 5HT1A receptor imaging; 4 of the BD subjects were rescanned following mood stabilizer treatment. We have developed satisfactory compartmental models for pixelwise determination of volume of distribution and have developed a method for defining regions of interest that will be semi-automated and thus independent of operator bias. The image data were analyzed for the BD versus control comparisons. The results include showing prominent reductions in 5HT1A receptor binding in the anterior and posterior cingulate cortices and the insula in bipolar disorder. The 5HT1A receptors in these regions play important roles in regulating emotional behavior. During the upcoming year the effects of serotonin transporter gene polymorphisms on this response will be characterized. In addition, the neuropsychological assessments from this study comparing depressed and healthy subjects have shown deficits in the unmedicated unipolar and bipolar depressed patients that are consistent with dysfunction of the amygdala, ventral anterior cingulate cortex, and orbital cortex. Specifically, unmedicated depressed patients displayed deficits in inhibiting inappropriate responses to affective stimuli that was not present in the healthy control sample suggesting an attentional bias towards these stimuli. The unmedicated depressed sample also required more time to deliberate on a risk-based task, consistent with findings in frontal lesion patients. In addition, imaging with the serotonin transporter radioligand progressed to permit characterization of the presynaptic portion of the serotonin system. An additional 12 subjects with unipolar depression, 6 subjects with bipolar depression and 17 healthy controls have been studied using this new method. These results showed for the first time a marked reduction in 5HTT sites in the brainstem and an increase in 5HTT binding in the anterior cingulate in bipolar depression. A manuscript describing these results has been prepared for publication. Finally, we have begun to characterize the relationship between ovarian steroids and 5HTT and 5HT1A receptor binding in women who develop post partum depression and menstrual related mood disorders. These data have shown that the imaging measures are sensitive to ovarian steroids. This work is being conducted in collaboration with Drs. Peter Schmidt and David Rubinow at NIH and with Drs. Eydie Moses and Walter Kaye at University of Pittsburgh.

大量证据表明，在惊恐障碍(PD)、创伤后应激障碍(PTSD)和抑郁症中，5-HT1A(5-HT1A)受体功能异常。本方案通过正电子发射断层扫描(PET)和5-HT1A受体放射配基[F-18]Fc-WAY100635在惊恐障碍、创伤后应激障碍、单相和双相抑郁中评估5-HT1A结合潜力，来研究体内5-HT1A异常的药理学基础。由于中枢5-HT1a受体密度被皮质酮注射和应激介导的皮质酮分泌下调，我们评估了HPA轴的活性，以确定5-HT1a受体的下调是否与PD、PTSD和MDD的皮质醇高分泌相关。在未服药的帕金森病、创伤后应激障碍和抑郁症患者或健康志愿者中，获得了5-HT1A结合的PET图像。注射([F-18]FCWAY)后，用PET数据的双组织室模型计算5-HT1a受体的分布体积。比较了整个抑郁组和对照组的5-HT1a受体在海马区、杏仁核、腹侧ACC和眼眶皮质的分布体积。用线性回归分析5-HT1a受体分布体积与唾液皮质醇、5-HT1a受体分布体积与脑脊液促肾上腺皮质激素释放激素(CRH)浓度的关系。 在过去的一年里，另外12名MDD患者和6名BD患者进入了这项研究，进行了5HT1A受体成像；其中4名BD患者在接受情绪稳定剂治疗后重新扫描。我们已经开发了令人满意的隔室模型，用于象素地确定分布体积，并开发了一种定义感兴趣区域的方法，该方法将是半自动的，因此不受操作员偏见的影响。图像数据被分析用于BD与对照组的比较。结果显示，双相情感障碍患者扣带回皮质前、后和脑岛的5HT1a受体结合显著减少。这些区域的5HT1a受体在调节情绪行为方面起着重要作用。在即将到来的一年中，5-羟色胺转运体基因多态对这一反应的影响将被表征。 此外，这项研究对抑郁症和健康受试者进行的神经心理学评估显示，未经药物治疗的单相和双相抑郁症患者存在缺陷，这与杏仁核、腹侧前扣带回皮质和眼眶皮质的功能障碍一致。具体地说，未经药物治疗的抑郁症患者在抑制对情感刺激的不适当反应方面表现出缺陷，这在健康对照样本中不存在，表明对这些刺激存在注意力偏差。未服用药物的抑郁样本也需要更多的时间来考虑基于风险的任务，这与额叶病变患者的发现一致。 此外，5-羟色胺转运体放射性配基的成像技术也取得了进展，可以对5-羟色胺系统的突触前部分进行表征。用这种新方法对12例单相抑郁症、6例双相抑郁症和17例健康对照进行了研究。这些结果首次显示双相抑郁患者脑干5HTT位点显著减少，前扣带回5HTT结合量增加。已经准备了一份描述这些结果的手稿，准备出版。 最后，我们已经开始对患有产后抑郁症和月经相关情绪障碍的女性的卵巢类固醇与5HTT和5HT1a受体结合的关系进行表征。这些数据表明，成像措施对卵巢类固醇很敏感。这项工作是与美国国立卫生研究院的彼得·施密特和大卫·鲁比诺博士以及匹兹堡大学的艾迪·摩西和沃尔特·凯博士合作进行的。