5-HT1B receptor function in OCD

5-HT1B 受体在强迫症中的功能

基本信息

批准号：
8204762
负责人：
Christopher John Pittenger
金额：
$ 17.7万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-10 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204762
关键词：
Acoustics Acute Affect Affinity Agonist Animals Attenuated Binding Biological Markers Brain Chronic Clinic Data Development Diagnostic Disease Fluoxetine Functional disorder Genes Genetic Genetic Polymorphism Gilles de la Tourette syndrome Gold Human Image Investigation Knowledge Ligands Link Literature Measurement Measures Membrane Minority Modeling Morbidity - disease rate Nature Neurobiology Neurons Neurotransmitters Obsessive-Compulsive Disorder Other Genetics Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Play Population Positron-Emission Tomography Process Publishing Relative (related person)Reporting Rodent Role Schizophrenia Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Agonists Serotonin Receptor 5-HT1B Severities Specificity Sumatriptan Symptoms System Testing Therapeutic Agents base disorder risk endophenotype in vivo insight instrument neuropsychiatry neurotransmission novel prepulse inhibition presynaptic public health relevance radioligand receptor receptor function research study serotonin receptor standard care

项目摘要

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is prevalent and severe, affecting approximately 2% of the population worldwide and producing substantial morbidity even when optimally treated. Serotonin reuptake inhibitors (SRIs) form the mainstay of pharmacotherapy for the disorder; serotonin agonists can exacerbate symptoms; and genetic studies suggest that abnormalities in the serotonin system may contribute to the disorder. However, the nature of any disruption in serotoninergic modulation in OCD remains poorly understood. The 5-HT1B receptor may play a critical role in this regard: the 5-HT1B/1D agonist sumatriptan has been shown to exacerbate OCD symptoms in several studies; and a number of genetic investigations have provided suggestive evidence that a polymorphism in the 5-HT1B gene is associated with OCD risk. 5-HT1B agonists disrupt prepulse inhibition (PPI), a measure of sensorimotor gating that is attenuated in OCD (as well as in several other neuropsychiatric conditions), in animals; and this disruption is ameliorated by chronic treatment with SSRIs - which is standard treatment for OCD. We hypothesize that functional abnormalities of the 5-HT1B receptor contribute to OCD. Measurement of this receptor in vivo in humans has been impossible until very recently, with the development and characterization at Yale of a novel positron emission tomography (PET) ligand, [11C] P943, with nanomolar affinity and good specificity for the 5-HT1B receptor. We propose to image 5-HT1B receptors by [11C] P943 PET in 15 medication-free, non-depressed OCD patients and 15 matched controls. This PET investigation will be enhanced by linking it to two OCD-relevant functional measures. First, we will assess symptom severity in all patients, using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The Y-BOCS was developed in our clinic in the 1980s and remains the gold-standard instrument for rating OCD symptoms. Second, we will assess PPI in all patients and controls. PPI has been shown to be blunted in patients with OCD. While it is not specific - it is also blunted in Tourette syndrome and schizophrenia, among other conditions - it is unique among candidate OCD endophenotypes in that it has been shown, in studies in animals, to be impaired by 5-HT1B agonists. This leads us to hypothesize that 5-HT1B receptor abnormalties may be linked to both OCD symptomatology and to blunted PPI; we expect PPI to correlate negatively with 5- HT1B binding potential. By investigating the 5-HT1B receptor in vivo in humans with OCD and seeking to correlate it with functional measures, we believe that this study will provide important new insight into the dysregulation of serotoninergic neurotransmission in this disorder. This investigation will thereby inform neurobiological models of this prevalent disorder. Through such advances, new treatments can be developed to aid the substantial minority of patients who receive little benefit from existing therapies. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive disorder (OCD) is common and leads to profound suffering; it can be treated with medications that target serotonin, but many patients get little benefit from this or other established treatments. We will examine a particular brain receptor for serotonin, the 5-HT1B receptor, in the brains of patients with OCD, using positron emission tomography. Better understanding of abnormalities in the serotonin system in OCD will pave the way for new pharmacological treatments of this severe neuropsychiatric disorder.

描述（由申请人提供）：强迫症 (OCD) 普遍且严重，影响着全世界约 2% 的人口，即使得到最佳治疗，也会产生相当大的发病率。血清素再摄取抑制剂 (SRI) 是该疾病药物治疗的支柱； 5-羟色胺激动剂会加剧症状；遗传学研究表明，血清素系统的异常可能会导致这种疾病。然而，对于强迫症中血清素能调节的任何破坏的性质仍然知之甚少。 5-HT1B 受体可能在这方面发挥关键作用：多项研究表明 5-HT1B/1D 激动剂舒马普坦会加剧强迫症症状；许多基因研究提供了提示性证据，表明 5-HT1B 基因的多态性与强迫症风险相关。 5-HT1B 激动剂会破坏动物的前脉冲抑制 (PPI)，这是一种感觉运动门控的测量方法，在强迫症（以及其他几种神经精神疾病）中会减弱；这种破坏可以通过长期使用 SSRIs 治疗来改善——这是强迫症的标准治疗方法。我们假设 5-HT1B 受体的功能异常会导致强迫症。直到最近，耶鲁大学开发并表征了一种新型正电子发射断层扫描 (PET) 配体 [11C] P943，对 5-HT1B 受体具有纳摩尔亲和力和良好的特异性，在人体体内测量这种受体一直是不可能的。我们建议通过 [11C] P943 PET 对 15 名未服用药物、非抑郁的 OCD 患者和 15 名匹配的对照者进行 5-HT1B 受体成像。通过将 PET 调查与两项与强迫症相关的功能测量联系起来，将得到加强。首先，我们将使用耶鲁-布朗强迫量表 (Y-BOCS) 评估所有患者的症状严重程度。 Y-BOCS 是我们诊所于 20 世纪 80 年代开发的，至今仍然是评估强迫症症状的黄金标准工具。其次，我们将评估所有患者和对照的 PPI。研究表明，强迫症患者的 PPI 会减弱。虽然它不具有特异性，在抽动秽语综合症和精神分裂症等疾病中也会减弱，但它在候选强迫症内表型中是独一无二的，因为在动物研究中，它已被证明会受到 5-HT1B 激动剂的损害。这使我们推测 5-HT1B 受体异常可能与 OCD 症状和 PPI 减弱有关；我们预计 PPI 与 5-HT1B 结合潜力呈负相关。通过研究强迫症患者体内的 5-HT1B 受体并寻求将其与功能测量相关联，我们相信这项研究将为这种疾病中血清素能神经传递失调提供重要的新见解。这项研究将为这种普遍疾病的神经生物学模型提供信息。通过这些进步，可以开发新的治疗方法来帮助绝大多数从现有疗法中获益甚少的患者。公共卫生相关性：强迫症 (OCD) 很常见，会导致深重的痛苦；它可以用针对血清素的药物治疗，但许多患者从这种或其他既定治疗中获益甚微。我们将使用正电子发射断层扫描检查强迫症患者大脑中血清素的特殊大脑受体，即 5-HT1B 受体。更好地了解强迫症中血清素系统的异常将为这种严重神经精神疾病的新药物治疗铺平道路。