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.

摘要 无序重复的行为和思维模式是许多神经精神疾病的特征， 包括强迫症(OCD)和抽动症(TS)等抽动障碍。 强迫症、强迫症和抽搐与皮质-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。 多条证据表明多巴胺(DA)及其受体在TS和强迫症中调节失调，但更多 目前仍不清楚，尤其是在强迫症方面。我们最近在小鼠模型上的研究中出现了新的见解。 与HDC基因突变相关的一种罕见遗传形式的TS和强迫症的病理生理学。平行 在这些小鼠(体外~3H拉氯必利结合)和少量HDC成人携带者中的研究 TS(11C-PHNO PET显像)突变显示黑质D2/D3受体表达上调。 以前的工作表明，D3上调可能代表了对慢性DA过量的反应，并且在 苍白球(GP)。在与强迫症无关的受试者中，11C-PHNO PET成像显示了一种独特的模式： 与SN中D2/D3受体的结合增加，但在GP中不结合，以及以前未见的 腹侧纹状体/伏隔核。我们推测伏隔核中的DA信号调节失调可能 导致不正常的奖励处理，这是我们最近在强迫症患者身上的特征。 这些试点数据不足以得出最终结论；它们需要确认，这是 目前的提议旨在实现。我们对DA受体重叠但不同模式的初步发现 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显像：15名强迫症患者，15名TS/TICS患者，15名同时患有两种强迫症患者 和抽搐(经常合并)，以及15名健康对照。这将允许我们执行几个 分析，所有这些都牢牢地植根于我们的试点数据。首先，我们将比较有和没有抽搐的个体；我们 预计在SN和GP中发现D2/D3结合增加，这将扩大我们在 罕见的TS相关HDC突变更普遍地发生在抽动障碍患者中，因此构成了罕见的真 从病理生理学的动物模型到人类的新洞察力。第二，我们将比较 患有和不患有强迫症的个体；我们预计腹侧纹状体的受体异常与 强迫症的症状，而结合在GP将与抽动共病有关。最后，我们将使用 跨整个数据集的连续症状测量，表征D2/D3异常的模式，这些异常可能 跨越传统的诊断类别。 这些研究将新的发现与最先进的方法结合在一起，以促进我们对 多巴胺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障碍。