Imaging the Serotonin System in Obsessive-Compulsive Disorder

描述（由申请人提供）：强迫症是一种普遍的、慢性的、致残的疾病。功能性脑成像研究表明，强迫症是由包括眶额皮质（OFC）、尾状核和丘脑在内的脑回路故障引起的。因为唯一已知的减轻强迫症症状的药物是5-羟色胺再摄取抑制剂（SRIs），人们一直假设强迫症是由大脑5-羟色胺（5-HT）系统的异常引起的。然而，尚不清楚SRIs是否通过纠正5-HT功能障碍或通过增强5-HT对脑回路的调节来减轻强迫症症状，而脑回路的潜在功能障碍与5-HT无关。强迫症的5-羟色胺假说在很大程度上尚未得到验证，部分原因是历史上很难直接检查活人大脑中的5-羟色胺系统。神经受体成像技术的进步现在允许使用正电子发射断层扫描（PET）和特定的放射配体来可视化人类的大脑神经化学。利用这项技术，首席研究员Blair Simpson博士与合作研究者Marc Laruelle博士合作，对强迫症患者大脑5-羟色胺系统的不同方面进行了成像。初步数据表明，强迫症与OFC中一种受体（5-HT2A受体）的可用性降低有关；然而，这些令人兴奋的初步发现需要在更大的样本中得到证实。这项RO1应用的具体目的是利用PET和5-HT2A受体的特定放射配体，量化24名强迫症患者和24名匹配对照的5-HT2A受体的区域分布（[1 lC]MDL 100907）。如果这项研究证实强迫症与OFC中5-HT2A受体可用性降低有关，那么这些数据将为强迫症中5-HT传递改变提供直接证据，并首次指出OFC突触后异常。这项研究的数据将促进我们对强迫症大脑机制的理解，并有助于为开发更好的治疗这种致残疾病的神经生物学基础。

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder is a prevalent, chronic, and disabling disorder. Functional brain imaging studies suggest that OCD results from a malfunctioning brain circuit that includes the orbitofrontal cortex (OFC), the caudate nucleus, and the thalamus. Because the only medications known to reduce OCD symptoms are serotonin reuptake inhibitors (SRIs), it has been hypothesized that OCD is caused by an abnormality in the brain serotonin (5-HT) system. However, it remains unclear whether SRIs reduce OCD symptoms by correcting 5-HT dysfunction or by enhancing 5-HT modulation of brain circuits whose underlying dysfunction is unrelated to 5-HT. The 5-HT hypothesis of OCD remains largely untested, in part because it has been historically difficult to examine directly the 5-HT system in the living human brain. Advances in neuroreceptor imaging techniques now permit visualization of brain neurochemistry in humans using positron emission tomography (PET) and specific radioligands. Using this technology, Dr. Blair Simpson, the Principal Investigator, has worked with Dr. Marc Laruelle, a Co-investigator, to image different aspects of the brain 5-HT system in OCD subjects. Preliminary data suggest that OCD is associated with decreased availability of one type of receptor, the 5-HT2A receptor, in the OFC; however, these exciting preliminary findings require confirmation in a larger sample. The specific aim of this RO1 application is to quantify the regional distribution of 5-HT2A receptors in 24 patients with OCD and 24 matched controls using PET and a specific radioligand for 5-HT2A receptors ([1 lC]MDL 100907). If this study confirms that OCD is associated with decreased 5-HT2A receptor availability in the OFC, these data would provide direct evidence for altered 5-HT transmission in OCD and point for the first time to a postsynaptic abnormality in the OFC. Data from this study will advance our understanding of the brain mechanisms of OCD and help build a neurobiological foundation for the development of better treatments for this disabling condition.