5-HT1B receptor function in OCD

描述（由申请人提供）：强迫症（OCD）是一种普遍而严重的疾病，影响着全球约2%的人口，即使在最佳治疗下也会产生大量的发病率。5 -羟色胺再摄取抑制剂（SRIs）是治疗该疾病的主要药物；血清素激动剂可加重症状；基因研究表明，血清素系统的异常可能会导致这种疾病。然而，强迫症中5 -羟色胺调节的任何破坏的性质仍然知之甚少。5-HT1B受体可能在这方面起着关键作用：在几项研究中，5-HT1B/1D激动剂舒马匹坦已被证明会加重强迫症症状；许多遗传学研究已经提供了提示证据，表明5-HT1B基因的多态性与强迫症风险有关。5-HT1B激动剂破坏动物的脉冲前抑制（PPI），这是一种感觉运动门控的测量，在强迫症（以及其他几种神经精神疾病）中减弱；这种干扰可以通过服用ssri类药物的慢性治疗得到改善——这是强迫症的标准治疗方法。我们假设5-HT1B受体的功能异常与强迫症有关。直到最近，随着耶鲁大学开发和表征一种新型正电子发射断层扫描（PET）配体[11C] P943，具有纳米摩尔亲和力和对5-HT1B受体的良好特异性，在人体体内测量这种受体是不可能的。我们建议通过[11C] P943 PET对15名无药物治疗的非抑郁强迫症患者和15名匹配的对照组进行5-HT1B受体成像。这种PET调查将通过将其与两种强迫症相关的功能措施联系起来而得到加强。首先，我们将使用耶鲁-布朗强迫症量表（Y-BOCS）评估所有患者的症状严重程度。Y-BOCS是20世纪80年代在我们诊所开发的，至今仍是评估强迫症症状的金标准工具。其次，我们将评估所有患者和对照组的PPI。PPI在强迫症患者中表现迟钝。虽然它不是特异性的——它在图雷特综合症和精神分裂症以及其他疾病中也会变钝——但在候选的强迫症内表型中，它是独一无二的，因为在动物研究中，它被5-HT1B激动剂破坏。这导致我们假设5-HT1B受体异常可能与强迫症症状和PPI钝化有关；我们预计PPI与5- HT1B结合电位呈负相关。通过研究强迫症患者体内的5-HT1B受体，并寻求其与功能指标的相关性，我们相信这项研究将为该疾病中血清素能神经传递失调提供重要的新见解。因此，这项研究将为这种流行疾病的神经生物学模型提供信息。通过这些进步，新的治疗方法可以开发出来，以帮助从现有治疗方法中获益甚微的大量少数患者。

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.