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纹状体内过量的多巴胺，但我们对多巴胺 D2 受体 (D2R) 在该疾病中的潜在机制知之甚少。一些影像学和尸检研究表明，与健康对照相比，精神分裂症患者的 D2R 密度升高，然而，这些发现并不一致，有人认为它们可能与之前接触抗精神病药物而不是与疾病过程更相关。本身。 然而，抗精神病药阻断 D2R 后阳性症状的缓解表明， D2R 信号传输可能会受到损害。可以解释这一现象的一种机制是内化受损。 D2R 内化是一种机制，使细胞能够将受体从细胞表面收回到胞质溶胶中，使它们不再受到多巴胺刺激。最近的研究，包括遗传、分子和尸检研究，表明 D2R 内化可能在精神分裂症中受损。这些发现现在需要对 D2R 贩运在精神分裂症中的作用进行进一步的临床研究。 PET 成像与安非他明激发相结合可能提供一种研究人类 D2R 贩运的方法。 PET 成像通常用于通过测量安非他明激发后 D2R 放射性示踪剂的结合电位 (BPND) 的变化来评估多巴胺传输。 BPND 被认为反映了由于内源性多巴胺的竞争加剧而导致放射性示踪剂的直接位移。 然而，一些观察表明，这种位移不仅与多巴胺的竞争加剧有关，而且与 D2R 的内化有关。 这最初是通过观察发现苯丙胺诱导的多巴胺激增数小时后 BPND 仍然下降而提出的。这种 BPND 的“晚期”减少（安非他明后 e4 小时）已在包括啮齿动物、猫、猴子和人类在内的物种中观察到。对多种 D2R 放射性示踪剂的测试发现，内化 D2R 的亲和力平均比细胞表面结合的亲和力低约两倍，这一变化足以解释苯丙胺攻击后 BPND 的“晚期”下降。 与这一想法一致，在 D2R 内化缺陷的小鼠模型中进行的 PET 研究未能观察到“晚期”效应，表明这种成像范式可能提供有关 D2R 内化的信息。 该提案的目的是探讨 D2R 运输受损在精神分裂症多巴胺能异常中发挥关键作用的假设。 我们建议在苯丙胺激发（0.5 mg/kg，口服）后的基线、3 小时和 8 小时使用 PET、[11C]雷氯必利对 15 名精神分裂症患者和 15 名健康对照进行成像。我们假设精神分裂症患者 BPND 的“晚期”下降会减弱，这反映了精神分裂症患者 D2R 运输受损，很可能与 D2R 内化受损有关。 如果成功，这一系列研究可能会为精神分裂症的病理生理学提供新的见解。