Serotonin 1B Receptor Imaging in Major Depressive Disorder

重度抑郁症的血清素 1B 受体成像

• 批准号: 7842623
• 负责人: ALEXANDER NEUMEISTER
• 金额: $ 24.93万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-14 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842623
• 关键词: Animals; Antidepressive Agents; Anxiety; Applications Grants; Area; Attention; Binding; Binding Sites; Biological Markers; Biology; Brain; Chemicals; DSM-IV; Data; Depressed mood; Development; Disease; Disease Progression; Dose; Emotions; Foundations; Functional disorder; Future; Globus Pallidus; Hormones; Human; Image; Individual; Injection of therapeutic agent; Learning; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Mental Depression; Methods; Modeling; Monitor; Mood Disorders; Neurons; Neurotransmitters; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Play; Positron-Emission Tomography; Process; Relative (related person); Rest; Risk; Role; Serotonin; Serotonin Receptor 5-HT1B; Serotonin Receptor Binding; Severities; Sleep; Stress; Symptoms; Therapeutic Agents; Therapeutic Effect; Time; Treatment Efficacy; Work; base; brain cell; cortico-limbic circuits; design; drug development; in vivo; interest; mood regulation; neurotransmitter release; novel; novel therapeutics; public health relevance; radioligand; radiotracer; receptor; receptor binding; receptor function; sex

DESCRIPTION (provided by applicant): The serotonin type 1B (5-HT1B) receptor has been implicated in the pathogenesis of major depressive disorder (MDD). Highest concentrations of 5-HT1B receptors are found in the globus pallidus in humans. The globus pallidus has received attention recently given its functional and anatomical connection to the mesolimbic circuit which is believed to be involved in the pathophysiology of MDD. Abnormal modulation of neurotransmitter release as a consequence of dysfunctional 5-HT1B receptors in the neuronal circuits which have been shown to play a role in the pathophysiology of MDD may at least partially explain the potential neurophysiologic dysfunction underlying depression. The 5- HT1B receptor may also be a candidate target for drug development. Even though animal studies and studies in human suggest an important role for the 5-HT1B receptor in the pathogenesis of MDD it is not clear at all whether such models constitute relevant models for MDD in humans. The selective 5-HT1B receptor radioligand, [11C] CE-142,943, permits for the first time in vivo assessment of central 5-HT1B receptor binding using positron emission tomography (PET). This proposal is a 2-year study involving 10 medication-free, symptomatic subjects with current MDD according to DSM-IV criteria, and 10 individually matched healthy control subjects. All subjects will undergo one magnetic resonance imaging (MRI) scan, and one [11C] CE-142,943 PET scan under resting conditions. This study will provide important new information about the role of 5- HT1B receptors in the pathophysiology of MDD. Moreover, we believe that this study will generate important novel results which we plan to use as basis for subsequent studies that aim to determine the abnormal processes which underlie mood disorders, guide initial dosing of new therapeutic agents and that are central to predict symptom onset, monitor disease progression and assess the efficacy of therapeutic agents. PUBLIC HEALTH RELEVANCE: The neurotransmitter serotonin plays an important role in the development of depression. Serotonin is one of the brain's natural chemicals. Serotonin binds to serotonin receptors (binding sites) type 1B on brain cells to regulate emotion, anxiety, sleep, and stress hormones. With the use of positron emission tomography (PET) and administration of a radiotracer, we are able to measure the number of serotonin 1b receptors in the brain. Following the injection of the radiotracer, the PET scanner will detect the radiotracer present in brain areas. This information will be used to create pictures of the brain showing the distribution of serotonin type 1B receptors in the brain. This method allows to determining whether people with depression show a different number of serotonin 1b receptors in the brain as compared to healthy people without depression or other psychiatric illnesses. This study will help not only to learning more about the biology of depression, but may ultimately help to find better treatments for people with depression.

描述（由申请人提供）：5-羟色胺1B （5-HT1B）受体与重度抑郁症（MDD）的发病机制有关。在人类苍白球中发现最高浓度的5-HT1B受体。由于苍白球在功能和解剖学上与中脑边缘回路的联系，最近受到了人们的关注，中脑边缘回路被认为参与了重度抑郁症的病理生理。神经回路中5-HT1B受体功能失调导致的神经递质释放异常调节已被证明在重度抑郁症的病理生理中发挥作用，这至少可以部分解释抑郁症潜在的神经生理功能障碍。5- HT1B受体也可能是药物开发的候选靶点。尽管动物研究和人体研究表明5-HT1B受体在MDD发病机制中起重要作用，但这些模型是否构成人类MDD的相关模型尚不清楚。选择性5-HT1B受体放射配体[11C] CE-142,943首次允许使用正电子发射断层扫描（PET）在体内评估中央5-HT1B受体结合。本研究是一项为期2年的研究，包括10名符合DSM-IV标准的无药物治疗、有症状的重度抑郁症患者，以及10名单独匹配的健康对照患者。所有受试者将在静息条件下进行一次磁共振成像（MRI）扫描和一次[11C] CE-142,943 PET扫描。本研究将为5- HT1B受体在重度抑郁症病理生理中的作用提供重要的新信息。此外，我们相信这项研究将产生重要的新结果，我们计划将其作为后续研究的基础，旨在确定情绪障碍背后的异常过程，指导新治疗剂的初始剂量，以及预测症状发作，监测疾病进展和评估治疗剂疗效的核心。公共卫生相关性：神经递质血清素在抑郁症的发展中起重要作用。血清素是大脑的一种天然化学物质。5 -羟色胺与1B型5 -羟色胺受体（结合位点）结合，调节情绪、焦虑、睡眠和应激激素。通过使用正电子发射断层扫描（PET）和放射性示踪剂，我们能够测量大脑中血清素1b受体的数量。在注入放射性示踪剂后，PET扫描仪将检测到存在于大脑区域的放射性示踪剂。这些信息将用于绘制大脑的图片，显示1B型血清素受体在大脑中的分布。这种方法可以确定抑郁症患者与没有抑郁症或其他精神疾病的健康人相比，大脑中血清素1b受体的数量是否有所不同。这项研究不仅有助于更多地了解抑郁症的生物学，而且可能最终有助于为抑郁症患者找到更好的治疗方法。

项目成果

The Serotonin 1B Receptor: A New Target for Depression Therapeutics?

• DOI: 10.1016/j.biopsych.2011.02.020
• 发表时间: 2011-04
• 期刊: Biological Psychiatry
• 影响因子: 10.6
• 作者: J. Murrough;A. Neumeister

Association of posttraumatic stress disorder with reduced in vivo norepinephrine transporter availability in the locus coeruleus.

• DOI: 10.1001/jamapsychiatry.2013.399
• 发表时间: 2013-11
• 期刊: JAMA PSYCHIATRY
• 影响因子: 25.8
• 作者: Pietrzak, Robert H;Gallezot, Jean-Dominique;Ding, Yu-Shin;Henry, Shannan;Potenza, Marc N;Southwick, Steven M;Krystal, John H;Carson, Richard E;Neumeister, Alexander
• 通讯作者: Neumeister, Alexander

The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding.

早期创伤暴露对5-羟色胺1B受体表达的影响，通过选择性放射性结合降低。

• DOI: 10.1001/archgenpsychiatry.2011.91
• 发表时间: 2011-09
• 期刊: ARCHIVES OF GENERAL PSYCHIATRY
• 作者: Murrough, James W.;Czermak, Christoph;Henry, Shannan;Nabulsi, Nabeel;Gallezot, Jean-Dominique;Gueorguieva, Ralitza;Planeta-Wilson, Beata;Krystal, John H.;Neumaier, John F.;Huang, Yiyun;Ding, Yu-Shin;Carson, Richard E.;Neumeister, Alexander
• 通讯作者: Neumeister, Alexander

Reduced ventral striatal/ventral pallidal serotonin1B receptor binding potential in major depressive disorder.

• DOI: 10.1007/s00213-010-1881-0
• 发表时间: 2011-02
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Murrough, James W.;Henry, Shannan;Hu, Jian;Gallezot, Jean-Dominique;Planeta-Wilson, Beata;Neumaier, John F.;Neumeister, Alexander
• 通讯作者: Neumeister, Alexander

Recent progress in understanding the pathophysiology of post-traumatic stress disorder: implications for targeted pharmacological treatment.

• DOI: 10.1007/s40263-013-0051-4
• 发表时间: 2013-03
• 期刊: CNS DRUGS
• 影响因子: 6
• 作者: Bailey, Christopher R.;Cordell, Elisabeth;Sobin, Sean M.;Neumeister, Alexander
• 通讯作者: Neumeister, Alexander