Probing dopamine D2 receptor trafficking in schizophrenia

描述（由申请人提供）：大量工作都集中在精神分裂症患者纹状体内过量的多巴胺上，但我们对多巴胺D2受体（D2 R）参与疾病的潜在机制知之甚少。一些成像和尸检研究表明，与健康对照组相比，精神分裂症患者的D2 R密度升高，然而，这些发现并不一致，有人认为它们可能与既往暴露于抗精神病药物有关，而不是与疾病过程本身有关。 然而，抗精神病药阻断D2 R后阳性症状的缓解表明， D2 R信号可能会受到损害。一种可能解释这一现象的机制是内化受损。D2 R内化是一种使细胞能够将受体从细胞表面撤回到胞质溶胶中的机制，因此它们不再可用于多巴胺刺激。最近的研究，包括遗传，分子和死后研究，表明D2 R内化可能在精神分裂症中受损。这些发现现在需要进一步的临床研究D2 R贩运在精神分裂症中的作用。 PET成像结合安非他明挑战可能提供一种方法来研究D2 R贩运的人。 PET成像通常用于通过测量安非他明激发后D2 R放射性示踪剂的结合电位（BPND）的变化来评估多巴胺传递。 BPND被认为反映了由于来自内源性多巴胺的竞争增加而导致的放射性示踪剂的直接置换。 然而，一些观察结果表明，位移不仅与多巴胺的竞争增加有关，而且与D2 R的内化有关。 这一点最初是由观察结果表明的，即在安非他明诱导多巴胺激增后数小时，BPND仍然降低。在包括啮齿动物、猫、猴和人类在内的物种中观察到BPND的这种“晚期”降低（安非他明后4小时）。广泛的D2 R放射性示踪剂的测试发现，平均约2倍低亲和力的内化D2 R比细胞表面结合，足以解释的变化，在安非他明的挑战后，在BPND的“后期”减少。 与这一想法相一致，在D2 R内化缺陷的小鼠模型中的PET研究未能观察到“晚期”效应，这表明该成像范例可以提供关于D2 R内化的信息。 本研究的目的是探讨D2 R转运受损在精神分裂症多巴胺能异常中起关键作用的假说。 我们建议在基线、苯丙胺激发后3 h和8 h（0.5 mg/kg，PO）对15例精神分裂症患者和15例健康对照者进行PET成像，[11 C]雷氯必利。我们推测，在精神分裂症患者中，BPND的“晚期”下降将被钝化，反映了精神分裂症中受损的D2 R运输，最有可能与受损的D2 R内化有关。 如果成功的话，这一系列的研究可能会为精神分裂症的病理生理学提供新的见解。

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.