Muscarinic Cholinergic Receptor Imaging in Depression

几种证据汇聚在一起，暗示胆碱能系统在情感性疾病的病理生理学中发挥作用。在单相抑郁和双相抑郁的受试者中，类胆碱药物(即M受体激动剂、乙酰胆碱酯酶抑制剂)会加重抑郁的体征和症状，如烦躁不安、精神运动迟缓、注意力和记忆障碍、下丘脑-垂体-肾上腺轴多动和睡眠脑电异常(Janowsky等，1974；OverStreet，1993)。在健康受试者中，乙酰胆碱酯酶抑制剂毒扁豆碱会引起一系列抑郁症状，包括烦躁不安、神经衰弱、精神运动减慢、情绪不稳定、睡眠障碍、记忆力和注意力障碍，以及较高剂量时的流泪和抑郁。这些效应已被证明反映了毒扁豆碱受体的刺激(Davis等人，1976；Oppenheim等人，1979；Risch等人，1981a)。模拟胆碱能也会加剧抑郁症动物模型中的行为绝望。相反，在一项安慰剂对照研究中，抗胆碱能药比哌啶改善了抑郁症的症状(Fleischhacker等人，1987年)。此外，毒扁豆碱类胆碱和一种富含胆碱的营养物质卵磷脂(磷脂酰胆碱)在双相情感障碍受试者中发挥抗躁狂作用。 与这些观察结果可能一致的是，抑郁症受试者对胆碱类药物表现出过敏反应。给予M胆碱能激动剂、ACh释放剂或乙酰胆碱酯酶抑制剂，在抑郁症受试者中，与健康对照组相比，对REM密度和潜伏期的影响被夸大(Berger等人，1983；Glin等人，1991a；Nofzinger等人，1997；Nurnberger等人，1989)。此外，与对照组相比，躁狂和抑郁的双相情感障碍受试者都表现出对M胆碱能激动剂匹罗卡品的更高的瞳孔敏感性(Sokolski和Demet，1996)。 尽管有数据表明mAChR受体系统与情绪障碍有关，但在抑郁症受试者中还没有对中枢mAChR进行直接的体内研究。一种新型的PET放射性配体[18F]FP-TZTP是最近由Eckelman(2001a；b)开发的M2受体的选择性激动剂。由于M2受体的主要功能是作为突触前释放控制的自身受体，该受体的分布体积(V)的减少可能导致突触后M受体敏感性的增加。 该项目在过去一年中对目前患有严重抑郁障碍的抑郁症受试者、目前患有双相情感障碍的抑郁症受试者和精神健康对照组进行了一项关于M2受体分布体积的正电子发射计算机断层扫描(PET)研究，大约有25名受试者被研究。结果证实了中枢假设，即双相情感障碍患者M2受体V主要位于突触前的区域，即扣带回皮质、脑岛、胼胝体和腹侧纹状体。这些区域在其他研究中也被认为是胆碱能调节受损的区域，这些区域可能会导致异常的情绪和注意力处理，以及包括烦躁、焦虑和欣快感在内的情绪体验改变。因此，这些数据促进了对抑郁症病理生理学的了解。胆碱能受体异常的程度与情绪突显有关，这些受试者将情绪突显归因于积极和消极的词汇。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中的这种异常是由M2受体突变纯合的受试者特异性地解释的。我们现在正试图复制这一发现，并对表现出这种异常的双相情感障碍亚群进行表征。

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, [18F]FP-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 now attempting to replicate this finding and characterize the bipolar disorder subgroup that exhibits this abnormality.