Validation of beta2 containing nicotinic acetylcholinergic receptors as a potenti

描述(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点，即双相抑郁。目前，治疗双相抑郁的有效、有效的治疗方法寥寥无几。显然，在双相抑郁的药物治疗中，迫切需要新的分子靶点和后续的治疗方法。其中一个靶点是烟碱型乙酰胆碱能受体系统，它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原因有关，值得引起足够的重视。直到最近，由于后勤方面的原因，包括缺乏合适的配体，这一系统还不适合在人类身上进行研究。一种新型的单光子发射断层扫描(SPECT)烟碱型乙酰胆碱能受体(NAChR)放射配基的发展现在使我们能够检查该受体系统的一个重要方面：包含烟碱型乙酰胆碱能受体的？2亚单位。这些受体广泛存在于大脑中，并被认为在系统中发挥关键作用，特别是因为它们在情绪调节回路中的位置。因此，我们的主要目标是确定目前抑郁的双相情感障碍患者中含有nAChRs的2亚单位的可用性，并将他们与健康对照对象进行比较。我们建议在双相抑郁患者中对含有nAChRs的2个亚单位进行SPECT研究，以确定这一关键因素是否存在功能障碍。我们将研究18例双相抑郁患者和18例年龄匹配的健康对照组。所有受试者将接受一次核磁共振扫描和一次SPECT扫描，使用SPECT放射性配基[123I]5-I-A-85380来量化参与情绪调节回路的大脑区域中含有烟碱型乙酰胆碱能受体的2个亚单位。根据以前的研究和我们的初步数据显示，在单相和双相抑郁中，该系统存在显著缺陷，我们假设双相抑郁患者中含有nAChRs的β2亚单位与健康对照组相比会减少。这项研究的结果将使我们能够确定是否值得在更大的样本中追求这个分子目标。与公共卫生相关：很明显，迫切需要开发新的治疗靶点来更好地治疗双相抑郁，因为目前对双相抑郁几乎没有有效的、经过充分验证的治疗方法。这项研究将验证一个特殊的受体系统，烟碱型乙酰胆碱受体，可能在双相抑郁的原因中发挥核心作用。如果这被证明是成功的，那么就有可能开发出更新的抗抑郁药物来更好地治疗双相抑郁患者。

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.