5-HT1B receptor function in OCD

描述（由申请人提供）：强迫症（OCD）普遍且严重，影响全球约2%的人口，即使在最佳治疗时也会产生大量发病率。5-羟色胺再摄取抑制剂（SRIs）形成了该疾病药物治疗的支柱; 5-羟色胺激动剂可加重症状;遗传研究表明，5-羟色胺系统的异常可能导致该疾病。然而，在强迫症中，多巴胺能调节的任何中断的性质仍然知之甚少。5-HT 1B受体可能在这方面起着关键作用：5-HT 1B/1D激动剂舒马曲坦在几项研究中已被证明会加剧强迫症症状;一些遗传学研究提供了暗示性证据，表明5-HT 1B基因的多态性与强迫症风险有关。5-HT 1B激动剂破坏前脉冲抑制（PPI），这是一种在强迫症（以及其他几种神经精神疾病）中减弱的感觉运动门控措施;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。 我们假设5-HT 1B受体的功能异常有助于强迫症。直到最近，在耶鲁大学开发和表征了一种新的正电子发射断层扫描（PET）配体[11 C] P943，对5-HT 1B受体具有纳摩尔亲和力和良好的特异性，才能在人体内测量这种受体。我们建议在15名无药物、非抑郁的强迫症患者和15名匹配的对照者中通过[11 C] P943 PET对5-HT 1B受体进行成像。 通过将PET调查与两个OCD相关功能测量相联系，将加强PET调查。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是在20世纪80年代在我们的诊所开发的，并且仍然是评定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在强迫症患者中被证明是钝化的。虽然它不是特异性的-它在图雷特综合征和精神分裂症等疾病中也是钝化的-它在候选的强迫症内在表型中是独特的，因为它在动物研究中被证明会被5-HT 1B激动剂削弱。这使我们假设，5-HT 1B受体异常可能与强迫症和钝化的PPI，我们预计PPI与5-HT 1B结合潜力呈负相关。 通过研究5-HT 1B受体在体内的人与强迫症，并寻求其与功能的措施，我们相信，这项研究将提供重要的新的见解，在这种疾病的多巴胺能神经传递失调。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，可以开发新的治疗方法，以帮助从现有疗法中获益甚少的少数患者。 公共卫生相关性：强迫症（OCD）是常见的，并导致深刻的痛苦;它可以用靶向血清素的药物治疗，但许多患者从这种或其他既定的治疗中获益甚少。我们将使用正电子发射断层扫描技术来检查强迫症患者大脑中一种特殊的5-羟色胺受体，即5-HT 1B受体。更好地了解强迫症中5-羟色胺系统的异常将为这种严重的神经精神障碍的新药物治疗铺平道路。

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.