Probing dopamine D2 receptor trafficking in schizophrenia

探索精神分裂症中的多巴胺 D2 受体贩运

• 批准号: 8712557
• 负责人: Anissa Abi-Dargham
• 金额: $ 20万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-02 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712557
• 关键词: Accounting; Acute; Adopted; Affinity; Agonist; Amphetamines; Antipsychotic Agents; Autopsy; Binding; Cardiovascular system; Cell Surface Receptors; Cell surface; Cells; Clinical Research; Corpus striatum structure; Cytosol; Disease; Dopamine; Dopamine D2 Receptor; Exposure to; Felis catus; Figs - dietary; Functional disorder; Goals; Hour; Human; Hyperactive behavior; Image; Measures; Molecular Genetics; Monkeys; Patients; Phase; Plasma; Play; Population; Positron-Emission Tomography; Process; Raclopride; Receptor Cell; Receptor Signaling; Regulation; Relative (related person); Research; Rodent; Role; Scanning; Schizophrenia; Solid; Symptoms; Testing; absorption; healthy volunteer; insight; mouse model; neuroimaging; nonhuman primate; novel; public health relevance; radioligand; radiotracer; receptor; receptor density; receptor internalization; trafficking; transmission process

DESCRIPTION (provided by applicant): A large body of work has focused on excess dopamine within striatum of patients with schizophrenia but we know little about the underlying mechanistic involvement of dopamine D2 receptors (D2R) in the illness. Some imaging and postmortem studies have suggested that D2R density is elevated in patients with schizophrenia compared to healthy controls, however, these findings have not been consistent and it was argued that they may be more related to prior exposure to antipsychotics rather than to the disease process per se. Nevertheless, the alleviation of positive symptoms specifically after blockade of D2R by antipsychotics suggests that homeostatic regulation of D2R signaling is likely to be compromised. One mechanism that may explain this is impaired internalization. D2R internalization is a mechanism that enables the cell to retract the receptors from the cell surface into the cytosol so they are no longer available for dopamine stimulation. Recent research, including genetic, molecular and postmortem studies, suggests that D2R internalization may be impaired in schizophrenia. These findings now call for further clinical studies of the role of D2R trafficking in schizophrenia. PET imaging combined with amphetamine challenge may offer a way to study D2R trafficking in humans. PET imaging has been commonly used to assess dopamine transmission by measuring the change in binding potential ( BPND) of a D2R radiotracer after an amphetamine challenge. BPND is thought to reflect direct displacement of the radiotracer due to increased competition from endogenous dopamine. However, some observations have suggested that the displacement is not only related to increased competition from dopamine, but also to internalization of the D2Rs. This was initially suggested by the observation that BPND remains decreased several hours after the amphetamine induced dopamine surge. This "late phase" decrease (e4 hr after amphetamine) in BPND has been observed across species including rodents, cats, monkeys and humans. Tests of a wide range of D2R radiotracers found on average about two-fold lower affinity for internalized D2R than cell surface bound, a change sufficient to explain the "late phase" decrease in BPND after amphetamine challenge. Consistent with this idea, a PET study in a mouse model deficient in D2R internalization failed to observe the "late phase" effect, suggesting that this imaging paradigm may provide information about D2R internalization. The goal of this proposal is to explore the hypothesis that impaired D2R trafficking plays a critical role in the dopaminergic abnormalities in schizophrenia. We propose to image 15 patients with schizophrenia and 15 healthy controls with PET, [11C]raclopride, at baseline, 3 h, and 8 h after amphetamine challenge (0.5 mg/kg, PO). We hypothesize that the "late phase" decrease in BPND will be blunted in patients with schizophrenia, reflecting impaired D2R trafficking in schizophrenia, most likely related to impaired D2R internalization. If successful, this lin of research may provide novel insight to the pathophysiology of schizophrenia.

描述（由申请人提供）：大量工作集中在精神分裂症患者的纹状体内过量多巴胺，但我们对多巴胺D2受体（D2R）在疾病中的潜在机理介入一无所知。与健康对照组相比，一些成像和验尸研究表明，精神分裂症患者的D2R密度升高，但是，这些发现并不一致，有人认为它们可能与事先暴露于抗精神病药，而不是与疾病过程有关。 然而，抗精神病药对D2R封锁后特别缓解阳性症状表明，稳态调节 D2R信号传导可能会受到损害。一种可能解释的机制是内在化受损的。 D2R内在化是一种使细胞从细胞表面缩回细胞质的机制，因此不再可用于多巴胺刺激。最近的研究，包括遗传，分子和验尸研究，表明在精神分裂症中D2R内在化可能受到损害。现在，这些发现要求进一步研究D2R运输在精神分裂症中的作用。 宠物成像与苯丙胺挑战相结合，可能会提供一种研究人类贩运D2R的方法。 PET成像通常用于通过测量苯丙胺攻击后D2R放射性示例的结合电位（BPND）的变化来评估多巴胺的传播。 据认为，由于内源性多巴胺的竞争增加，BPND反映了放射性示踪剂的直接位移。 但是，一些观察结果表明，该位移不仅与多巴胺的竞争增加有关，而且与D2RS的内在化有关。 最初，观察到，苯丙胺诱导多巴胺激增几个小时后，BPND保持降低。在包括啮齿动物，猫，猴子和人类在内的物种中，已经观察到了BPND中这种“后期”减少（苯丙胺后的E4 HR）。比细胞表面结合的范围广泛的D2R放射性示踪剂的测试平均比细胞表面结合低约2倍，这种变化足以说明苯丙胺挑战后BPND的“后期”减少。 与这个想法一致，在D2R内部化缺陷的小鼠模型中的一项PET研究未能观察到“后期”效应，这表明此成像范式可能会提供有关D2R内在化的信息。 该提案的目的是探讨D2R贩运受损的假设在精神分裂症的多巴胺能异常中起着至关重要的作用。 我们建议在苯丙胺攻击后基线，3 h和8小时（0.5 mg/kg，po）对15例精神分裂症和15例健康对照患者进行[11C] raclopride的成像。我们假设精神分裂症患者的BPND的“后期”降低将钝化，反映了精神分裂症中D2R贩运受损的损害，这很可能与D2R内在化受损有关。 如果成功的话，这种研究可能会为精神分裂症的病理生理学提供新的见解。