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）：大量的工作集中在精神分裂症患者纹状体中过量的多巴胺，但我们对多巴胺D2受体（D2R）在该疾病中的潜在机制参与知之甚少。一些影像学和尸检研究表明，与健康对照组相比，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先前接触抗精神病药物有关，而不是与疾病过程本身有关。然而，特别是在抗精神病药物阻断D2R后，阳性症状的减轻表明，体内平衡调节