Muscarinic Cholinergic Receptor Imaging in Depression

抑郁症中的毒蕈碱胆碱能受体成像

基本信息

批准号：
7969388
负责人：
WAYNE C DREVETS
金额：
$ 19.58万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7969388
关键词：
3&apos Untranslated Regions Accounting Acetylcholinesterase Inhibitors Affective Age Agonist Animal Model Anti-Cholinergics Antimanic Agents Anxiety Area Attention Autoreceptors Behavioral Biological Bipolar Depression Bipolar Disorder Choline Cholinergic Receptors Cholinomimetics Clinical Corpus Callosum Data Development Diagnosis Dose Electroencephalography Emotional Euphoria Exhibits Functional disorder Genes Genetic Genetic Markers Genetic Polymorphism Genotype Goals Hyperactive behavior Hypersensitivity Image Impairment Insula of Reil Investigation Knowledge Lecithin Major Depressive Disorder Manic Manuscripts Maps Measures Memory Mood Disorders Muscarinic Acetylcholine Receptor Muscarinic Agonists Muscarinic M2 Receptor Muscarinics Mutation Neurobiology Neuropsychological Tests Nutrient Onset of illness Paper Pathogenesis Pattern Pharmaceutical Preparations Physostigmine Pilocarpine Positron-Emission Tomography Preparation Process Protocols documentation Publications Receptor Gene Recurrence Regulation Relative (related person)Risk Factors Role Sampling Seminal Serotonin Severities Short-Term Memory Signs and Symptoms Single Nucleotide Polymorphism Sleep Sleep disturbances Staging Subgroup System Testing Translations Unipolar Depression Variant Ventral Striatum base cholinergic cingulate cortex cohort controlled release density depressed depression depressive symptoms dysphoria emotional experience genetic association hypothalamic-pituitary-adrenal axis improved in vivo information processing memory recognition neuroimaging novel placebo controlled study postsynaptic presynaptic radioligand receptor receptor binding receptor function receptor sensitivity visual information

项目摘要

Several paths of evidence converge in implicating a role for the cholinergic system in the pathophysiology of affective illness. In both unipolar depressed and euthymic bipolar subjects, cholinomimetic drugs (i.e., muscarinic agonists, acetylcholinesterase inhibitors) exacerbate depressive signs and symptoms such as dysphoria, psychomotor retardation, impairment of attention and memory, hypothalamic pituitary adrenal axis hyperactivity and sleep EEG abnormalities (Janowsky et al., 1974; Overstreet, 1993). In healthy subjects, the acetylcholinesterase inhibitor physostigmine elicits a range of depressive symptoms including dysphoria, anergia, psychomotor slowing, emotional lability, sleep disturbances, memory and concentration impairment, and with higher doses, tearfulness and depression. These effects have been shown to reflect stimulation of muscarinic receptors (Davis et al., 1976; Oppenheim et al., 1979; Risch et al., 1981a). Cholinomimetics also exacerbate behavioral despair in putative animal models of depression. Conversely, the anticholinergic agent biperidine improved symptoms of depression in a placebo controlled study (Fleischhacker et al., 1987). Moreover, muscarinic cholinomimetics and a choline rich nutrient, lecithin (phosphatidylcholine) exert antimanic effects in bipolar subjects. Potentially consistent with these observations, depressed subjects exhibit hypersensitivity to cholinomimetic agents. Administration of muscarinic cholinergic agonists, ACh releasing agents or acetylcholinesterase inhibitors induce exaggerated effects on REM density and latency in depressed subjects than in healthy controls (Berger et al., 1983; Gillin et al., 1991a; Nofzinger et al., 1997; Nurnberger et al., 1989). In addition, both manic and depressed bipolar subjects show increased pupillary sensitivity to the muscarinic cholinergic agonist pilocarpine relative to controls (Sokolski and Demet, 1996). Despite the data implicating the mAChR receptor system in mood disorders, no direct in vivo investigations of the central mAChR have been performed in depressed subjects. A novel PET radioligand, 18FFP-TZTP was recently developed by Eckelman (2001a; b) as a selective agonist of M2 receptors. Because the M2 receptor functions predominantly as a presynaptic release-controlling autoreceptor, decreased distribution volume (V) of this receptor could conceivably give rise to increased postsynaptic muscarinic receptor sensitivity. This project conducted a PET study of M2 receptor distribution volume in currently depressed subjects with major depressive disorder, currently depressed subjects with bipolar disorder, and psychiatrically healthy controls, about 25 subjects being studied in the past one year. The results confirmed the central hypothesis that M2 receptor V is decreased in regions where they are primarily located presynaptically in depressed subjects with bipolar disorder relative to healthy controls, namely in the cingulate cortex, insula, corpus callosum, and ventral striatum. These regions have been implicated in other studies as areas where impaired cholinergic regulation may result in abnormal emotional and attentional processing and altered emotional experiences including dysphoria, anxiety and euphoria. As such these data advance knowledge regarding the pathophysiology of depression. The magnitude of the cholinergic receptor abnormality correlated with the emotional salience which these subjects attributed to positively and negatively valenced words. Two scientific manuscripts have been prepared and submitted to describe these findings. During this past year, we demonstrated that this abnormality in bipolar disorder is specifically accounted for by subjects who are homozygous for a mutation of the M2 receptor. We are preparing a manuscript describing this seminal finding. We are now attempting to replicate this finding of the relationship between M2 receptor binding and M2 receptor polymorphism genotype. Moreover, we noted that the bipolar subjects who had this genotype and the associated reduction in M2 receptor binding manifested a more disabling and severe form of bipolar depression. We will thus be characterizing the bipolar disorder subgroup that exhibits this abnormality and genotype to identify clinical and biological correlates of this group. If these findings can be replicated in our expanded sample, we may be able to establish a particularly severe, genetically identified subtype of bipolar disorder. This paper has now under reviewed for publication. Finally, the genetic sampling from the subjects in this neuroimaging study were used to identify single nucleotide polymorphisms (SNPs) associated with unipolar depression (MDD) in a sample enriched for the likelihood of having genetic liability for MDD based upon having recurrent illness and early age-at illness-onset. The associations discovered in this very-well characterized, enriched MDD sample were then replicated in a larger sample selected more generally according to MDD criteria alone. One genetic marker showed a significant dominance genetic association effect with the MDD diagnosis which also remained significatnt (p<0.004) after correcting for multiple testing. Replication testing in a second, larger sample of healthy controls (n=739) and MDD cases (n=1,915) derived from the STAR*D cohort, confirmed the association with this marker(p<0.02). The marker so implicated mapped to the HTR3C gene, which encodes expression of the serotonin type 3C receptor subunit. The SNP variation (A/G) of this marker is located in the 3 untranslated region, which has a cis/trans control region known to subserve regulatory mechanisms such as translation and transport. Our results suggest that variation in HTR3C is a risk factor for MDD. A paper describing this finding is in the final stages of preparation.

多种证据都表明胆碱能系统在情感疾病的病理生理学中发挥着作用。在单相抑郁和心境正常的双相受试者中，拟胆碱药物（即毒蕈碱激动剂、乙酰胆碱酯酶抑制剂）会加剧抑郁体征和症状，例如烦躁不安、精神运动迟缓、注意力和记忆力受损、下丘脑垂体肾上腺轴过度活跃和睡眠脑电图异常（Janowsky 等）等人，1974；奥弗斯特里特，1993）。在健康受试者中，乙酰胆碱酯酶抑制剂毒扁豆碱会引发一系列抑郁症状，包括烦躁、无力、精神运动减慢、情绪不稳定、睡眠障碍、记忆力和注意力障碍，剂量较高时会导致流泪和抑郁。这些效应已被证明反映了毒蕈碱受体的刺激（Davis 等人，1976；Oppenheim 等人，1979；Risch 等人，1981a）。拟胆碱药还会加剧假定的抑郁动物模型中的行为绝望。相反，在安慰剂对照研究中，抗胆碱能药物联哌啶改善了抑郁症状（Fleischhacker 等，1987）。此外，毒蕈碱拟胆碱剂和富含胆碱的营养素卵磷脂（磷脂酰胆碱）对双相情感障碍患者具有抗躁狂作用。抑郁症受试者对拟胆碱药物表现出超敏反应，这可能与这些观察结果一致。与健康对照组相比，服用毒蕈碱胆碱能激动剂、乙酰胆碱释放剂或乙酰胆碱酯酶抑制剂对抑郁受试者的 REM 密度和潜伏期产生更大的影响（Berger 等，1983；Gillin 等，1991a；Nofzinger 等，1997；Nurnberger等人，1989）。此外，与对照组相比，躁狂和抑郁双相受试者的瞳孔对毒蕈碱胆碱能激动剂毛果芸香碱的敏感性增加（Sokolski 和 Demet，1996）。尽管有数据表明 mAChR 受体系统与情绪障碍有关，但尚未在抑郁症受试者中进行中枢 mAChR 的直接体内研究。 Eckelman (2001a; b) 最近开发了一种新型 PET 放射性配体 18FFP-TZTP，作为 M2 受体的选择性激动剂。由于 M2 受体主要作为突触前释放控制自身受体发挥作用，因此该受体的分布体积 (V) 减少可能会导致突触后毒蕈碱受体敏感性增加。该项目对目前患有重度抑郁症的抑郁受试者、目前患有双相情感障碍的抑郁受试者以及精神健康对照者进行了 M2 受体分布体积的 PET 研究，在过去一年中对约 25 名受试者进行了研究。结果证实了中心假设，即相对于健康对照，双相情感障碍抑郁症受试者的 M2 受体 V 主要位于突触前的区域（即扣带皮层、岛叶、胼胝体和腹侧纹状体）减少。其他研究表明这些区域的胆碱能调节受损可能会导致情绪和注意力处理异常以及情绪体验改变，包括烦躁、焦虑和欣快感。因此，这些数据增进了有关抑郁症病理生理学的知识。胆碱能受体异常的程度与这些受试者归因于正价和负价词的情绪显着性相关。已经准备并提交了两份科学手稿来描述这些发现。在过去的一年里，我们证明了双相情感障碍的这种异常是由 M2 受体突变纯合的受试者造成的。我们正在准备一份描述这一开创性发现的手稿。我们现在正试图复制 M2 受体结合与 M2 受体多态性基因型之间关系的这一发现。此外，我们注意到，具有这种基因型和相关的 M2 受体结合减少的双相情感障碍受试者表现出更严重的双相抑郁症。因此，我们将表征表现出这种异常和基因型的双相情感障碍亚组，以确定该组的临床和生物学相关性。如果这些发现可以在我们扩大的样本中得到复制，我们也许能够建立一种特别严重的、基因鉴定的双相情感障碍亚型。该论文现已接受审查以供发表。最后，在这项神经影像学研究中，对受试者进行的基因采样被用来识别样本中与单相抑郁症 (MDD) 相关的单核苷酸多态性 (SNP)，该样本根据疾病复发和早年情况丰富了患有 MDD 遗传倾向的可能性- 发病时。在这个特征明确、丰富的 MDD 样本中发现的关联随后被复制到仅根据 MDD 标准更普遍选择的更大样本中。一种遗传标记显示出与 MDD 诊断显着的显性遗传关联效应，在校正多重测试后也仍然显着 (p<0.004)。在来自 STAR*D 队列的第二个更大样本的健康对照 (n=739) 和 MDD 病例 (n=1,915) 中进行的复制测试证实了与该标志物的关联 (p<0.02)。如此涉及的标记映射到 HTR3C 基因，该基因编码 5-羟色胺 3C 型受体亚基的表达。该标记的 SNP 变异 (A/G) 位于 3 个非翻译区，该区域具有一个顺式/反式控制区，已知可促进翻译和转运等调节机制。我们的结果表明 HTR3C 的变异是 MDD 的危险因素。描述这一发现的论文正处于准备的最后阶段。