Validation of beta2 containing nicotinic acetylcholinergic receptors as a potenti

含有烟碱乙酰胆碱能受体 β2 的有效性的验证

• 批准号: 7894612
• 负责人: Irina Esterlis
• 金额: $ 17.49万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894612
• 关键词: Acetylcholine; Age; Amygdaloid structure; Animals; Antidepressive Agents; Attention; Bipolar Depression; Bipolar Disorder; Brain; Brain region; Cholinergic Antagonists; Chronic; Data; Depressed mood; Development; Elements; Emission-Computed Tomography; Etiology; Family; Functional disorder; Gated Ion Channel; Hippocampus (Brain); Human; Hyperactive behavior; Individual; Ligands; Literature; Location; MRI Scans; Manuscripts; Mental Depression; Molecular; Molecular Target; Mood Disorders; Moods; Nicotinic Receptors; Patients; Pharmaceutical Preparations; Pharmacotherapy; Photons; Play; Process; Reporting; Role; Sampling; Scanning; Societies; Symptoms; System; Testing; Therapeutic; Unipolar Depression; Validation; base; burden of illness; cholinergic; depressive symptoms; effective therapy; man; new therapeutic target; non-smoker; non-smoking; novel; public health relevance; radioligand; receptor; receptor binding; therapeutic target; tomography

DESCRIPTION (provided by applicant): Bipolar disorder is a chronic, severe and devastating illness which exerts a crippling personal and financial toll on the individual, family and wider society. The main burden of illness in bipolar disorder is in the depressive pole i.e. bipolar depression. There are currently few effective, well-validated treatments for bipolar depression. It is clear that there is an urgent need for novel molecular targets and subsequently treatments in the pharmacotherapy of bipolar depression. One such target is the nicotinic acetylcholinergic receptor system which has been postulated to play a role in the pathophysiology of bipolar disorder. A number of recent studies implicate this system in the causation of bipolar disorder and it warrants justified attention. Until recently this system was not amenable to study in man due to logistical reasons including the lack of availability of appropriate ligands. The development of a novel single photon emission tomography (SPECT) nicotinic acetylcholinergic receptor (nAChR) radioligand now allows us to examine an important aspect of this receptor system; ¿2 subunit containing nicotinic acetylcholinergic receptors. These receptors are widespread in the brain and are assumed to play a key role in the system especially due to their location in mood regulating circuits. Our primary aim is therefore to determine ¿2 subunit containing nAChRs availability in patients with bipolar disorder, who are currently depressed and compare them with healthy control subjects. We propose a SPECT study of ¿2 subunit containing nAChRs in patients with bipolar depression to determine whether there is a dysfunction of this key element. We will study 18 patients with bipolar depression and 18 age-matched healthy control subjects. All subjects will have one MRI scan and one SPECT scan with the SPECT radioligand [123I]5-I-A-85380 to quantify ¿2 subunit containing nicotinic acetylcholinergic receptors in brain regions involved in mood regulating circuits. Based on previous studies and our preliminary data showing significant deficits of this system in unipolar and bipolar depression, we hypothesize that there will be a decrease in ¿2 subunit containing nAChRs in patients with bipolar depression compared with healthy control subjects. The results of this study will allow us to determine if this molecular target is worth pursuing in a larger sample. PUBLIC HEALTH RELEVANCE: It is clear that there is an urgent need for the development of novel therapeutic targets to better treat bipolar depression as there are currently few effective, well-validated treatments for bipolar depression. This study will validate one particular receptor system, the nicotinic acetylcholine receptor, as potentially having a central role in the causation of bipolar depression. If this proves successful then it would be possible to develop newer antidepressant drugs to better treat patients with bipolar depression.

描述（由申请人提供）：双相情感障碍是一种慢性，严重和毁灭性的疾病，对个人，家庭和更广泛的社会造成严重的个人和经济损失。双相情感障碍的主要疾病负担是在抑郁极，即双相抑郁症。目前，双相抑郁症的有效，有效的治疗方法很少。很明显，在双相抑郁症的药物治疗中，迫切需要新的分子靶点和后续治疗。其中一个靶点是尼古丁乙酰胆碱能受体系统，该系统被认为在双相情感障碍的病理生理学中发挥作用。最近的一些研究表明，这一系统与双相情感障碍的病因有关，值得引起合理的关注。直到最近，由于后勤原因，包括缺乏适当的配体，该系统不适合在人体中研究。一种新的单光子发射断层扫描（SPECT）烟碱乙酰胆碱能受体（nAChR）放射性配体的发展，现在允许我们研究这个受体系统的一个重要方面;包含烟碱乙酰胆碱能受体的<$2亚基。这些受体在大脑中广泛分布，并被认为在系统中发挥关键作用，特别是由于它们在情绪调节回路中的位置。因此，我们的主要目的是确定双相情感障碍患者（目前患有抑郁症）中含有nAChRs的<$2亚基的可用性，并将其与健康对照组进行比较。我们提出了一个SPECT研究的<$2亚基含有nAChRs的双相抑郁症患者，以确定是否有功能障碍的这一关键因素。我们将研究18名双相抑郁症患者和18名年龄匹配的健康对照者。所有受试者都将接受一次MRI扫描和一次使用SPECT放射性配体[123 I]5-I-A-85380进行的SPECT扫描，以量化参与情绪调节回路的大脑区域中含有尼古丁乙酰胆碱能受体的º 2亚基。基于先前的研究和我们的初步数据显示，该系统在单相和双相抑郁症中的显着缺陷，我们假设，与健康对照组相比，双相抑郁症患者中含有nAChRs的<$2亚基会减少。这项研究的结果将使我们能够确定这个分子靶点是否值得在更大的样本中进行研究。公共卫生关系：很明显，迫切需要开发新的治疗靶点以更好地治疗双相抑郁症，因为目前双相抑郁症的有效、经过充分验证的治疗方法很少。这项研究将验证一个特定的受体系统，烟碱乙酰胆碱受体，作为潜在的双相抑郁症的原因有一个核心作用。如果这被证明是成功的，那么就有可能开发出新的抗抑郁药物来更好地治疗双相抑郁症患者。