Imaging Alterations in Endocannabinoid Metabolism in Schizophrenia

精神分裂症内源性大麻素代谢的影像学改变

• 批准号: 8816894
• 负责人: Romina Mizrahi
• 金额: $ 14.66万
• 依托单位: CENTRE FOR ADDICTION AND MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816894
• 关键词: Animals; Antipsychotic Agents; Binding; Brain; CNR1 gene; Cannabinoids; Cannabis; Carbon; Cerebrospinal Fluid; Cerebrovascular Circulation; Chemicals; Clinical; Clinical Research; Cognitive deficits; Collaborations; Complex; Corpus striatum structure; Data; Disease; Dopamine; Dose; Drug Kinetics; Economics; Endocannabinoids; Enzymes; Epidemiologic Studies; Epidemiology; Etiology; Exhibits; Family; Future; Gatekeeping; Heterogeneity; Human; Human Volunteers; Hydrolysis; Image; Incidence; Individual; Investigation; Joints; Kinetics; Label; Lead; Life; Link; Magnetic Resonance Imaging; Measures; Metabolism; Modeling; Molecular; Neurotransmitters; Outcome Measure; Participant; Pathway interactions; Patient Care; Patients; Pharmacodynamics; Plasma; Play; Population; Positron-Emission Tomography; Prefrontal Cortex; Prevention; Property; Psychopathology; Psychotic Disorders; Radioactivity; Radiochemistry; Recording of previous events; Regulation; Reporting; Reproducibility; Research; Resolution; Risk; Risk Factors; Role; Safety; Schizophrenia; Severities; Signal Pathway; Signal Transduction; Site; Specificity; Stress; Symptoms; System; Testing; Therapeutic Agents; Time; Tissues; Tracer; Volunteer Group; anandamide; base; cannabinoid receptor; clinical infrastructure; cognitive function; density; dosimetry; fatty acid amide hydrolase; healthy volunteer; in vivo; indexing; inhibitor/antagonist; molecular imaging; neurochemistry; neuroimaging; neurotransmitter release; novel; novel strategies; novel therapeutic intervention; novel therapeutics; presynaptic; psychotic symptoms; public health relevance; radioligand; radiotracer; receptor expression; social; uptake; years lived with disability

DESCRIPTION (provided by applicant): While the role of dopamine in positive symptoms of schizophrenia (SCZ) is well established, it is increasingly recognized that cannabinoid signaling may also play a key role. Epidemiological studies have detected a twofold increase in the incidence of SCZ with early cannabis use, identifying it as a major trigger for the disease and thus providing the first link between cannabinoids and SCZ. The most studied of endocannabinoids (eCBs), anandamide (AEA), acts on the presynaptic CB1 receptors to modulate the release of neurotransmitters. Dramatic elevations of AEA were detected in cerebrospinal fluid of patients with SCZ in the midst of a psychotic episode, which normalize after psychosis resolution. Levels of AEA in the brain are tightly regulated through hydrolysis by the fatty acid amide hydrolase (FAAH) enzyme. FAAH therefore sets the tone of the eCB system. [11C]CURB, a carbon-11-labelled form of the potent irreversible FAAH inhibitor URB694, has recently been synthesized by our CAMH radiochemistry team and characterized for positron emission tomography (PET) imaging. The tracer exhibits high brain uptake, regional distribution that reflects known FAAH density, and excellent pharmacodynamic and pharmacokinetic properties, as established in animal studies. Furthermore, PET imaging in healthy volunteers (HV) was carried out to establish proof-of- concept, test-retest reproducibility and full body dosimetry, and to optimize kinetic modeling for [11C]CURB quantification. As the first radiotracer capable of assessing FAAH enzyme in-vivo, [11C]CURB goes beyond quantifying CB1 receptor expression by providing for the first time an index of AEA/FAAH in the living brain. We aim to measure FAAH in vivo by using [11C]CURB PET in antipsychotic-naive patients with SCZ. We hypothesize that [11C]CURB binding in the striatum and dorsolateral prefrontal cortex will be significantly lower in SCZ, as compared to HV. Additionally, we aim to explore the relation between regional FAAH levels and psychopathology and cognitive deficits in SCZ. Thirty-four participants (17 in SCZ and 17 in HV group) will undergo a 60 min [11C]CURB PET scan using a high-resolution research tomograph (HRRT). As previously established, the kinetics of [11C]CURB can be described with an irreversible two-tissue compartment model using metabolite-corrected [11C]CURB radioactivity in arterial plasma as input function, providing the reliable outcome measure ?k3. High resolution Magnetic Resonance Imaging (MRI) scans will provide an anatomical correlation needed to quantify regional tracer distribution in the PET image, as well as to measure regional cerebral blood flow. The proposed research will be the first exploration of changes in eCB signaling in a living brain evaluating for the first time AEA metabolism in SCZ. Our research is important since it may elucidate the neurochemical mechanism behind the role of cannabis in the onset of SCZ. This conceptual breakthrough would have significant impact on the field of psychosis, providing a new approach to treatment and prevention of SCZ.

描述（由申请人提供）：虽然多巴胺在精神分裂症（SCZ）阳性症状中的作用已得到充分证实，但人们越来越认识到大麻素信号传导也可能发挥关键作用。流行病学研究发现，早期使用大麻会使SCZ的发病率增加一倍，将其确定为该疾病的主要触发因素，从而提供了大麻素和SCZ之间的第一个联系。研究最多的内源性大麻素（eCB），大麻素（AEA），作用于突触前CB 1受体，调节神经递质的释放。在精神病发作期间，SCZ患者的脑脊液中检测到AEA显著升高，精神病消退后恢复正常。大脑中AEA的水平通过脂肪酸酰胺水解酶（FAAH）的水解作用进行严格调节。因此，FAAH确定了eCB系统的基调。[11 C]CURB是一种碳-11标记形式的强效不可逆FAAH抑制剂URB 694，最近由我们的CAMH放射化学团队合成，并用于正电子发射断层扫描（PET）成像。如动物研究中所确定的，示踪剂表现出高脑摄取、反映已知FAAH密度的区域分布以及优异的药效学和药代动力学特性。此外，在健康志愿者（HV）中进行PET成像，以建立概念验证、重测重现性 和全身剂量测定，并优化[11 C]CURB定量的动力学建模。作为第一个能够在体内评估FAAH酶的放射性示踪剂，[11 C]CURB通过首次提供活脑中AEA/FAAH的指数而超越了量化CB 1受体表达。我们的目的是测量FAAH在体内使用[11 C]CURB PET抗精神病药初治患者SCZ。我们假设，与HV相比，SCZ中纹状体和背外侧前额叶皮质中的[11 C]CURB结合率显著降低。此外，我们的目的是探讨区域FAAH水平和SCZ的精神病理学和认知缺陷之间的关系。34名受试者（SCZ组17名，HV组17名）将使用高分辨率研究断层扫描仪（HRRT）进行60分钟[11 C]CURB PET扫描。如前所述，[11 C]CURB的动力学可以用不可逆的两组织房室模型描述，该模型使用动脉血浆中代谢物校正的[11 C]CURB放射性作为输入函数，提供可靠的结果测量？k3。高分辨率磁共振成像（MRI）扫描将提供量化PET图像中区域示踪剂分布以及测量区域脑血流所需的解剖学相关性。这项研究将首次探索eCB信号在活体大脑中的变化，首次评估SCZ中的AEA代谢。我们的研究很重要，因为它可能阐明大麻在SCZ发病中的作用背后的神经化学机制。这一概念上的突破将对精神病领域产生重大影响，为SCZ的治疗和预防提供新的方法。