Muscarinic Cholinergic Receptor Imaging in Depression

抑郁症中的毒蕈碱胆碱能受体成像

• 批准号: 7594555
• 负责人: WAYNE C DREVETS
• 金额: $ 47.63万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 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/7594555
• 关键词: 3' 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 Agents; Cholinergic Receptors; Cholinomimetics; Clinical; Corpus Callosum; Data; Depressed mood; 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; Mental Depression; 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; Range; Rate; Receptor Gene; Recurrence; Regulation; Relative (related person); Risk Factors; Role; Sampling; Score; 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; depressive symptoms; dysphoria; emotional experience; genetic association; hypothalamic-pituitary-adrenal axis; improved; in vivo; memory recognition; neuroimaging; novel; placebo controlled study; postsynaptic; presynaptic; radioligand; receptor; receptor binding; receptor function; receptor sensitivity; roentgen equivalent man; visual information

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. 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.

几种证据途径融合在暗示胆碱能系统在情感疾病的病理生理学中的作用。 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等，1974； 1993年）。在健康的受试者中，乙酰胆碱酯酶抑制剂物理学会引起一系列抑郁症状，包括烦躁不安，疾病，精神运动降低，情绪稳定，睡眠障碍，记忆力和浓度障碍，以及较高的剂量，泪水和抑郁症。这些作用已被证明反映了毒蕈碱受体的刺激（Davis等，1976； Oppenheim等，1979； Risch等，1981a）。在假定的抑郁症动物模型中，胆碱酯仪也会加剧行为绝望。相反，在安慰剂对照研究中，抗胆碱能药物双吡啶改善了抑郁症状（Fleischhacker等，1987）。此外，毒蕈碱胆碱酯和富含胆碱的营养素，卵磷脂（磷脂酰胆碱）在双极受试者中发挥抗触发作用。 潜在的与这些观察结果一致的，抑郁症受试者表现出对胆碱成剂的过敏性。与健康对照组相比，毒液胆碱能激动剂，ACH释放剂或乙酰胆碱酯酶抑制剂诱导对抑郁症受试者的REM密度和潜伏期的影响（Berger等，1983; Gillin等，1991a; Nofzinger等，1997; Nofzinger等，1997; Nurnnurnberger et al an and and and and and and and and and and and of plestions dempers and rem密度和潜伏期。此外，躁狂和抑郁受试者均表明，相对于对照组，对毒蕈碱胆碱能激动剂毛虫的瞳孔敏感性提高（Sokolski和Demet，1996）。 尽管有数据暗示MACHR受体系统在情绪障碍中，但在抑郁症的受试者中尚未对中央MACHR进行直接的体内研究。 Eckelman（2001a; b）最近开发了一种新型的PET放射线，18FFP-TZTP是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的自身受体作用，因此该受体的分布体积降低可能会导致突触后毒蕈碱受体敏感性的提高。 该项目对当前患有严重抑郁症的受试者，目前患有双相情感障碍的受试者和精神健康对照组进行了M2受体分布量的PET研究，在过去一年中研究了25名受试者。结果证实了一个中心假设，即M2受体V在主要位于具有双相情感障碍的受试者中相对于健康对照组的抑郁症受试者，即在扣带回皮层，岛状call，callosum callos和腹侧。这些区域已与其他研究有关，因为胆碱能调节受损可能导致情绪和注意力处理异常，并改变了情绪经历，包括烦躁不安，焦虑和欣快。因此，这些数据提高了有关抑郁症的病理生理学的知识。胆碱能受体异常的大小与这些受试者的情绪显着性相关。已经准备了两个科学手稿，以描述这些发现。 在过去的一年中，我们证明了双相情感障碍的这种异常是由对M2受体突变纯合的受试者特别考虑的。我们正在准备一个描述这种开创性发现的手稿。 我们现在正在尝试复制M2受体结合与M2受体多态性基因型之间关系的发现。此外，我们注意到具有这种基因型的双极受试者以及M2受体结合的相关降低表现出了躁郁症抑郁症的更加残疾和严重的形式。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，以鉴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展的样本中复制，我们可能能够建立一个特别严重的遗传鉴定的躁郁症亚型。 最后，该神经影像学研究中的受试者的遗传采样用于鉴定与单极抑郁症（MDD）相关的单核苷酸多态性（SNP），该样品富含基于复发性疾病和早期疾病患者对MDD具有遗传责任的样本。然后，仅根据MDD标准，在更普遍地选择的较大样本中复制了在这种非常井的特征，富集的MDD样品中发现的关联。 一个遗传标记显示出与MDD诊断的显着优势遗传关联效应，在校正多次测试后，该遗传标记也显着（P <0.004）。在第二个较大的健康对照样本（n = 739）和MDD病例（n = 1,915）中进行的复制测试证实了与此标记的关联（p <0.02）。 含义映射到HTR3C基因的标记，该基因编码5-羟色胺3C受体亚基的表达。该标记的SNP变化（A/G）位于3个未翻译区域，该区域具有已知可提供调节机制（例如翻译和运输）的顺式/反式控制区域。我们的结果表明，HTR3C的变化是MDD的危险因素。描述这一发现的论文处于准备的最后阶段。