Serotonin/Benzodiazepin Receptor Imaging In Panic Dis

有证据表明，在惊恐障碍(PD)、创伤后应激障碍(PTSD)和抑郁症(MDD)中，5-HT1A受体和苯二氮卓(BZD)受体功能异常。支持BZD/GABA受体功能障碍在焦虑症中作用的证据来自分别显示BZD激动剂和拮抗剂的抗焦虑和致焦虑特性的研究。BZD受体敏感性已被证明在焦虑症患者中降低。用正电子发射断层扫描(PET)和单光子发射计算机断层扫描(SPECT)进行的脑成像研究表明，帕金森病和创伤后应激障碍患者BZD受体结合减少。然而，在人类中，5-HT1A受体结合紊乱的相互作用与BZD受体结合改变之间的联系尚未被探索，到目前为止，还没有关于惊恐障碍或创伤后应激障碍患者5-HT1A受体结合潜力的研究。这项研究将通过使用PET和[11C]flumazenil和[18F]Fc-WAY100635([18F]FCWAY)来比较PD、PTSD和MDD患者与健康对照组之间的BZD受体和5-HT1A受体结合潜力，从而促进对PD和PTSD神经生物学的了解。由于中枢5-HT1a受体密度在啮齿类动物中被皮质酮注射和应激介导的皮质酮分泌下调，因此将评估HPA轴的活性，以确定5-HT1a受体下调是否与PD、PTSD和MDD的皮质醇高分泌相关。 由于该项目之前报道的5-HT1A受体结合电位在惊恐障碍中显著降低，现在修改了方案，以检查5-HTT结合是否也在Pancic障碍中异常，如用PET和[11C]DASB测量的那样。5HTT结合以前从未在恐慌症中被评估过，尽管已知与大脑中5HTT结合并促进5HTT功能的抗抑郁药物可以改善恐慌症症状。5-HT1A的功能此外，为了补充BZD受体结合的测量，这种受体的神经递质，即伽马-氨基丁酸(GABA)的浓度正在使用磁共振波谱(GABA-MRS)在大脑中进行测量。这些研究具有开拓性，因为它们是第一次在内侧前额叶皮质区域获得，这些区域与正常和病理性焦虑状态的神经生物学以及抑郁症的病理生理学有关。结果，在一组患有严重抑郁障碍的受试者和一组患有恐慌症的受试者中，获得了GABA-MRS图像。 在过去的一年里，我们已经获得了另外10名惊恐障碍患者和11名健康对照的BZD受体的PET-Flumazenil图像。目前正在分析BZD受体图像数据。此外，我们还获得了两名惊恐障碍受试者的5HTT图像。最后，对17例抑郁症患者、15例惊恐障碍患者和18例健康对照进行了GABA-MRS成像。 这些实验的一个主要发现是，从GABA-MRS图像中获得的GABA浓度在严重抑郁障碍患者中显著降低，特别是在那些符合忧郁亚型标准的患者中。 在明年，我们计划公布惊恐障碍中的苯二氮卓类受体成像数据，并将公布创伤后应激障碍中苯二氮类药物和5HT-1a受体结合数据的结果(这些图像的分析等待其他健康对照的扫描，扫描已于2005年9月完成)。我们还将在2005年10月完成GABA-MRS数据的获取，并将公布这些研究的数据。最后，我们将在焦虑症样本和健康对照组中检查这些功能相连的受体物种之间的相互关系。

Evidence suggests that serotonin1A (5-HT1A) receptor and benzodiazepine (BZD) receptor function is abnormal in panic disorder (PD), postraumatic stress disorder (PTSD), and depression (MDD). Evidence arguing for a role of BZD/GABA receptor dysfunction in anxiety disorders comes from studies showing anxiolytic and anxiogenic properties of BZD agonists and antagonists, respectively. BZD receptor sensitivity has been shown to be reduced in patients with anxiety disorders. Brain imaging studies using positron emission tomography (PET) and single photon emissison computed tomography (SPECT) suggest decreased BZD receptor binding in PD and PTSD. Yet, association between disturbed interactions between 5-HT1A receptor binding and alterations in BZD receptor binding has not been explored in humans, and so far there are no studies about 5-HT1A receptor binding potential in patients with panic disorder or PTSD. This study will advance knowledge regarding the neurobiology of PD and PTSD by employing PET and [11C]flumazenil and [18F]FC-WAY100635 ([18F]FCWAY) to compare BZD receptor and 5-HT1A receptor binding potential between PD, PTSD, and MDD patients and healthy controls. 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 will be assessed to determine whether down-regulation of 5-HT1A receptors correlates with cortisol hypersecretion in PD, PTSD, and MDD. Because of the previously reported finding from this project that the 5-HT1A receptor binding potential was markedly decreased in panic disorder, the protocol was amended to now examine whether the serotonin transporter (5-HTT) binding also is abnormal in pancic disorder, as measured using PET and [11C]DASB. The 5HTT binding has never previously been assessed in panic disorder, even though antidepressant drugs which bind to the 5HTT site in the brain and facilitate 5HT function are known to improve panic disorder symptoms. 5-HT1A function In addition, to complement the measures of BZD recepor bindingg, the concentration of the neurotransmitter for this receptor, namely gama-amino-butyric acid (GABA) is being measured in the brain using magnetic resonance spectroscopy (GABA-MRS). These studies are pioneering in that they are being obtained for the first time in medial prefrontal cortical regions that have been implicated in the neurobiology of normal and pathological anxiety states as well as in the pathophysiology of depression. As a result, the GABA-MRS images are being obtained in a comparison group of subjects with major depressive disorder as well as in a group who has panic disorder. During the past year, we have obtained PET-flumazenil images of the BZD receptor in an additional 10 subjects with panic disorder and 11 healthy controls. The BZD receptor image data currently are being analyzed. In addition, we obtained 5HTT images in two subjects with panic disorder. Finally, the GABA-MRS images have been acquired in 17 patients with major depressive disorder, 15 patients with panic disorder and 18 healthy controls. A major finding from these experiments is that the GABA concentration obtained from the GABA-MRS images is markedly decreased in major depressive disorder subjects, and particularly in those patients who meet criteria for the melancholic subtype. During the next year we plan to publish the benzodiazepine receptor imaging data in panic disorder, and will publish the results of the benzodiazepine and 5HT-1A receptor binding data in PTSD (the analyses of these images awaited the scanning of additional healthy controls, which has been completed in 9/05). We also will complete the acquistion of the GABA-MRS data in October of 2005 and will publish the data from these studies. Finally, we will examine interrelationships between these functionally linked receptor species in anxiety disordered samples and in healthy controls.