Probing dopamine D2 receptor trafficking in schizophrenia

描述(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)在疾病中的潜在机制知之甚少。一些成像和尸检研究表明，精神分裂症患者的D2R密度比健康对照组高，然而，这些发现并不一致，有人认为它们可能更多地与先前接触抗精神病药物有关，而不是疾病过程本身。然而，抗精神病药物阻断D2R后阳性症状的缓解表明，体内平衡调节 D2R信令可能会受到损害。一种可能解释这一现象的机制是内化受损。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浆中，从而使它们不再可用于多巴胺刺激。最近的研究，包括遗传学、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。宠物成像结合苯丙胺挑战可能提供一种研究D2R贩卖人口的方法。PET成像通常用于通过测量苯丙胺刺激后D2R放射性示踪剂结合电位(BPND)的变化来评估多巴胺的传递。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，一些观察表明，这种置换不仅与来自多巴胺的竞争增加有关，还与D2Rs的内化有关。这最初是通过观察苯丙胺诱导的多巴胺激增几个小时后BPND仍然减少而提出的。在包括啮齿动物、猫、猴子和人类在内的所有物种中都观察到了BPND的这种“晚期”下降(安非他明后4小时)。对广泛的D2R放射性示踪剂的测试发现，内化的D2R的亲和力平均比细胞表面结合的亲和力低两倍，这一变化足以解释苯丙胺攻击后BPND“晚期”下降的原因。与这一想法一致的是，在D2R内化缺陷的小鼠模型上进行的PET研究未能观察到“后期”效应，这表明这种成像范式可能提供了关于D2R内化的信息。这项建议的目的是探索D2R运输受损在精神分裂症的多巴胺能异常中起关键作用的假说。我们建议想象15名精神分裂症患者和15名健康对照的PET，[11C]拉氯普利，在苯丙胺攻击(0.5 mg/kg，PO)后的基线，3小时和8小时。我们假设BPND的“晚期”下降在精神分裂症患者中会减弱，反映了精神分裂症中D2R运输的受损，很可能与D2R内化受损有关。如果成功，这项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.