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（由适用提供）：双相情感障碍是一种慢性，严重和破坏性的疾病，对个人，家庭和广泛的社会造成了个人和经济损失。躁郁症中疾病的主要烧伤是在抑郁杆中，即躁郁症抑郁症。目前，对双极抑郁症的有效，有效的验证治疗方法很少。显然，迫切需要新的分子靶标，然后在双相抑郁症的药物治疗中进行治疗。这样的靶标是烟碱乙酰胆碱能受体系统，该系统已被认为在躁郁症的病理生理中发挥作用。最近的许多研究暗示了该系统是躁郁症的原因，并且值得关注。直到最近，由于后勤原因，该系统还不能接受人类研究，包括缺乏适当的配体。现在，新型的单光子发射断层扫描（SPECT）烟碱乙酰胆碱能受体（NACHR）放射性物体的发展使我们能够检查该受体系统的重要方面。 2个含有烟碱乙酰胆碱能受体的亚基。这些受体在大脑中广泛宽度，并被认为在系统中起关键作用，尤其是由于它们在情绪调节电路中的位置。因此，我们的主要目的是确定二2个亚基，其中含有NACHRS的可用性，这些患者目前抑郁症，并将其与健康对照受试者进行比较。我们提出了一项对双极抑郁症患者中含有NACHR的亚基的SPECT研究，以确定该关键因素是否功能障碍。我们将研究18例躁郁症抑郁症患者和18岁年龄匹配的健康对照受试者。所有受试者将进行一项MRI扫描和一个SPECT扫描[123i] 5-i-A-85380，以量化2个亚基，其中含有含烟碱乙酰胆碱能受体，涉及情绪调节循环的大脑区域。根据先前的研究和我们的初步数据，显示该系统在单极和双相抑郁症中的明显缺陷，我们假设与健康对照组相比，双极抑郁症患者中含有NACHR的2个亚基含有NACHR。这项研究的结果将使我们能够确定在较大样本中是否值得追求该分子靶标。公共卫生相关性：很明显，迫切需要开发新型的治疗靶标，以更好地治疗双相抑郁症，因为目前几乎没有有效的，有效的验证疗法来治疗双极抑郁症。这项研究将验证一种特定的受体系统，即烟碱乙酰胆碱受体，可能在双相抑郁症的原因中具有核心作用。如果证明这是成功的，那么有可能开发新的抗抑郁药来更好地治疗双极抑郁症患者。