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 emission 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 panic disorder, as measured using PET and [11C]DASB. The 5HTT binding has not 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. In addition, to complement the measures of BZD receptor binding, 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 completed PET-flumazenil imaging of the BZD receptor in an additional 10 subjects with panic disorder and 11 healthy controls. The BZD receptor image data have been analyzed and a publication describing the results is in preparation. In addition, we obtained 5HTT images in 12 subjects with panic disorder. Finally, the GABA-MRS images acquired in patients with major depressive disorder were completed and these data were submitted for publication. In addition, a total of 20 patients with panic disorder and 18 healthy controls were scanned using GABA-MRS imaging, and the analysis for these data are being completed. A major finding from these experiments is that the prefrontal cortex GABA and Glx (glutamine plus glutamate) concentrations obtained from the GABA-MRS images are markedly decreased in major depressive disorder subjects. This was the first study to demonstrate this abnormality in the prefrontal cortical regions previously implicated in depression. 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. We also will complete the acquistion of the GABA-MRS data in subjects scanned before and after the GABA-enhancing agent, gabapentin. Finally, we will examine interrelationships between these functionally linked receptor species in anxiety disordered samples and in healthy controls.
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