Dysregulation of dopamine receptors in the basal ganglia in OCD and tic disorders: Positron Emission Tomography with [11C]-PHNO

强迫症和抽动障碍中基底神经节多巴胺受体的失调：[11C]-PHNO 正电子发射断层扫描

• 批准号: 10672999
• 负责人: Christopher John Pittenger
• 金额: $ 76.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672999
• 关键词: Address; Adult; Agonist; Alleles; Anhedonia; Animal Model; Basal Ganglia; Behavior; Behavioral; Binding; Brain; Categories; Characteristics; Chronic; Clinical; Comparative Study; Corpus striatum structure; Data; Data Set; Development; Diagnosis; Diagnostic; Disease; Dissociation; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug Targeting; Functional disorder; Ganglia; Genes; Genetic; Genetic study; Gilles de la Tourette syndrome; Globus Pallidus; Histidine Decarboxylase; Human; Image; Individual; Intervention; Knockout Mice; Knowledge; Ligands; Measures; Methodology; Modeling; Morbidity - disease rate; Mus; Mutation; Nature; Nonsense Mutation; Nucleus Accumbens; Obsession; Obsessive-Compulsive Disorder; Patients; Pattern; Penetrance; Positron-Emission Tomography; Raclopride; Severities; Signal Transduction; Structure; Substantia nigra structure; Symptoms; Syndrome; System; Testing; Thalamic structure; Tic disorder; Time; Tracer; Translations; Up-Regulation; Ventral Striatum; Work; antagonist; clinically significant; comorbidity; compulsion; genetic architecture; imaging study; in vivo; independent component analysis; individualized medicine; insight; mouse model; neurochemistry; neuroeconomics; neuropsychiatric disorder; neuropsychiatry; novel; putamen; receptor; receptor binding; recruit; response; reward processing; symptomatology; tic related

ABSTRACT Disordered repetitive patterns of behavior and thought characterize numerous neuropsychiatric conditions, including obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) and other tic disorders. Obsessions, compulsions, and tics are associated with dysregulation of the cortico-basal ganglia circuitry, but the underlying pathophysiological details remain poorly understood. Several lines of evidence implicate dysregulation of dopamine (DA) and its receptors in TS and OCD, but much remains unclear, especially in OCD. New insight has arisen from our recent studies in a mouse model of the pathophysiology of a rare genetic form of TS and OCD associated with a mutation in the Hdc gene. Parallel studies in these mice (ex vivo 3H raclopride binding) and in a small number of adult carriers of the Hdc mutation with TS (11C-PHNO PET imaging) revealed upregulation of D2/D3 receptors in the substantia nigra, where previous work suggests that D3 upregulation may represent a response to chronic DA excess, and in the globus pallidus (GP). In unrelated subjects with OCD, 11C-PHNO PET imaging revealed a distinct pattern: increased binding to D2/D3 receptors in the SN but not in the GP, and a previously uncharacterized increase in the ventral striatum/nucleus accumbens. We speculate that dysregulated DA signaling in the accumbens may contribute to abnormal reward processing, which we have recently characterized in individuals with OCD. These pilot data are not sufficient powered for definitive conclusions; they require confirmation, which the current proposal seeks to achieve. Our tentative finding of overlapping but distinct patterns of DA receptor abnormality in two related neuropsychiatric conditions sets the stage for an important comparative study. We will perform 11C-PHNO PET imaging in 60 adult subjects: 15 with OCD, 15 with TS/tics, 15 with both OCD and tics (which are frequently comorbid), and 15 healthy controls. This will permit us to perform several analyses, all firmly grounded in our pilot data. First, we will compare individuals with and without tics; we expect to find increased D2/D3 binding in the SN and GP, which would extend our findings in carriers of the rare TS-associated Hdc mutation to tic patients more generally and thus constitute a rare instance of true translation from an animal model of pathophysiology to new insight in humans. Second, we will compare individuals with and without OCD; we expect receptor abnormalities in the ventral striatum to be related to OCD symptomatology, while binding in the GP will be associated with tic comorbidity. Finally, we will use continuous symptom measures across the full dataset, characterizing patterns of D2/D3 abnormality that may cut across traditional diagnostic categories. These studies bring together new findings with state-of-the-art methodologies to advance our understanding of how dysregulation in DA and its receptors contributes to disordered repetitive patterns of behavior and thought in two common neuropsychiatric disorders.

抽象的 行为和思维的无序重复模式是许多神经精神疾病的特征， 包括强迫症（OCD）和抽动秽语综合征（TS）以及其他抽动障碍。 强迫观念、强迫行为和抽动与皮质基底神经节回路的失调有关，但是 潜在的病理生理学细节仍然知之甚少。 多项证据表明 TS 和 OCD 中多巴胺 (DA) 及其受体的失调，但很多证据 仍不清楚，尤其是在强迫症中。我们最近对小鼠模型的研究产生了新的见解 与 Hdc 基因突变相关的 TS 和 OCD 的罕见遗传形式的病理生理学。平行线 在这些小鼠（离体 3H 雷氯必利结合）和少数成年 Hdc 携带者中进行的研究 TS 突变（11C-PHNO PET 成像）显示黑质中 D2/D3 受体的上调， 先前的研究表明 D3 上调可能代表对慢性 DA 过量的反应，并且在 苍白球 (GP)。在患有 OCD 的无关受试者中，11C-PHNO PET 成像揭示了一种独特的模式： SN 中与 D2/D3 受体的结合增加，但 GP 中没有，并且先前未表征的增加 腹侧纹状体/伏隔核。我们推测伏隔核中的 DA 信号失调可能 导致奖励处理异常，我们最近在强迫症患者中进行了表征。 这些试点数据不足以得出明确的结论；他们需要确认， 目前的提案力求实现。我们初步发现 DA 受体重叠但不同的模式 两种相关神经精神疾病的异常为一项重要的比较研究奠定了基础。 我们将对 60 名成人受试者进行 11C-PHNO PET 成像：15 名患有强迫症，15 名患有 TS/抽动症，15 名同时患有强迫症 和抽动症（通常合并症），以及 15 名健康对照。这将使我们能够执行多项操作 分析，全部以我们的试点数据为基础。首先，我们将比较有抽动症和没有抽动症的个体；我们 预计在 SN 和 GP 中发现 D2/D3 结合增加，这将扩展我们在 SN 和 GP 携带者中的发现 抽动症患者中罕见的 TS 相关 Hdc 突变更普遍，因此构成了真正的罕见病例 从病理生理学的动物模型转化为人类的新见解。其次，我们来比较一下 患有和不患有强迫症的人；我们预计腹侧纹状体的受体异常与 OCD 症状学，而在 GP 中的结合将与抽动合并症相关。最后，我们将使用 整个数据集中的连续症状测量，表征可能的 D2/D3 异常模式 跨越传统的诊断类别。 这些研究将新发现与最先进的方法结合起来，以增进我们对 DA 及其受体的失调如何导致行为和思维的无序重复模式 两种常见的神经精神疾病。