Imaging Brain Cannabinoid Receptors (CB1) in Schizophrenia

描述（由申请人提供）：汇聚的证据表明精神分裂症的大麻素假说包括外源性和内源性因素。根据更好地了解外源性假说，1）大麻素可以在健康个体中产生全方位的短暂精神分裂症样效应，2）大麻素可以加剧精神病症状，引发复发并对精神分裂症患者的病程产生负面影响，3）暴露于大麻可能会导致精神分裂症的风险。支持内源性假说的证据包括：1）脑脊液（CSF）内源性大麻素水平升高，2）精神分裂症患者脑大麻素受体（CB 1 R）区域改变的尸检结果。此外，精神分裂症患者也更容易受到大麻素的行为和认知影响;这一发现可能反映了内源性大麻素系统的异常。CB 1 R可用性的尸检结果与一些显示减少的研究混合在一起，而其他研究则显示不同大脑区域的增加。此外，抗精神病药物对精神分裂症患者CB 1 R可用性的影响尚不清楚，CB 1 R可用性与精神分裂症患者行为和认知症状之间的关系尚未得到充分研究。 最近开发的几种CB 1 R特异性正电子发射断层扫描（PET）配体，包括[11 C]OMAR，提供了直接测量CB 1 R在体内精神分裂症的可用性的工具。假设：精神分裂症患者的CB 1 R可用性低于对照组。此外，未用药的精神分裂症患者相对于用药（抗精神病药治疗）患者具有较低的CB 1 R可用性。最后，在精神分裂症患者中，记忆和精神病的测量将分别与海马和腹侧纹状体区域的CB 1 R可用性相关。目的：使用经验证的CB 1 R PET配体[11 C]OMAR和高分辨率研究性断层扫描（HRRT）PET，比较精神分裂症患者（包括未服用抗精神病药物的患者亚组）与年龄、性别、体重指数（BMI）和吸烟状态匹配的健康对照的CB 1 R体内利用率。在精神分裂症受试者中，症状和认知的测量将与相关大脑区域中的CB 1 R可用性相关。初步结果：我们已经开发了适当的方法，[11 C]OMAR数据的定量分析，并建议，[11 C]OMAR是一个合适的示踪剂，研究CB 1 R系统在人类。精神分裂症患者在几个大脑区域中的CB 1 R可用性降低，其中苍白球>前扣带皮层>壳核>海马>杏仁核的降低最大。由于这些结果存在于未接受药物治疗的受试者中，因此观察到的变化不能归因于正在接受的抗精神病药物的影响。 公共卫生相关性：精神分裂症患者的大脑大麻素受体系统可能发生改变。我们建议成像脑大麻素受体（CB 1 R）在精神分裂症患者与对照组相比。此外，还将研究抗精神病药物对CB 1 Rs的影响，以及CB 1 Rs与精神分裂症患者症状测量之间的关系。

DESCRIPTION (provided by applicant): Converging lines of evidence suggest a cannabinoid hypothesis of schizophrenia that includes exogenous and endogenous elements. According to the better know exogenous hypothesis, 1) cannabinoids can produce a full range of transient schizophrenia-like effects in healthy individuals, 2) cannabinoids can exacerbate psychotic symptoms, trigger relapses and negatively impact the course of illness in schizophrenia patients, and 3) exposure to cannabis may contribute to the risk of developing schizophrenia. Evidence supporting an endogenous hypothesis includes 1) the presence of elevated cerebrospinal fluid (CSF) endocannabinoid levels and 2) post-mortem findings of regional alterations in brain cannabinoid receptors (CB1R) in schizophrenia. Additionally, schizophrenia patients are also more vulnerable to the behavioral and cognitive effects of cannabinoids; a finding that may reflect abnormalities in the endocannabinoid system. The post mortem findings of CB1R availability have been mixed with some studies showing decreases, and others showing increases in different brain regions. Furthermore, the effects of antipsychotic medication on CB1R availability in schizophrenia are not clear, and the relationship between CB1R availability and behavioral and cognitive symptoms in schizophrenia has not been adequately studied. The recent development of several CB1R specific Positron Emission Tomography (PET) ligands, including [11C]OMAR, provide the tools to directly measure CB1R availability in schizophrenia in vivo. Hypothesis: Schizophrenia patients will have lower CB1R availability than controls. Furthermore, unmedicated schizophrenia patients will have lower CB1R availability relative to medicated (antipsychotic- treated) patients. Finally, in schizophreni patients, measures of memory and psychosis will correlate with CB1R availability in hippocampus and ventrostriatal regions, respectively. Aims: To compare CB1R availability in vivo in schizophrenia patients (including a subgroup of patients not taking antipsychotic medications), to age, gender, Body Mass Index (BMI), and smoking status matched healthy controls using the validated CB1R PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT) PET. In schizophrenia subjects, measures of symptoms and cognition will be correlated to CB1R availability in relevant brain regions. Preliminary Results: We have developed appropriate methods for quantitative analysis of [11C]OMAR data and suggest that [11C]OMAR is an appropriate tracer with which to investigate the CB1R system in humans. Schizophrenia patients have decreased CB1R availability in several brain regions, with the greatest reductions in the pallidum > anterior cingulate cortex > putamen > hippocampus > amygdala. Since the findings were present in subjects who were unmedicated, the observed changes cannot be attributed to the effects of ongoing antipsychotic medications. PUBLIC HEALTH RELEVANCE: The brain cannabinoid receptor system may be altered in schizophrenia. We propose to image brain cannabinoid receptors (CB1R) in individuals with schizophrenia compared to controls. Furthermore, the effects of antipsychotic medications on CB1Rs, and the relationship between CB1Rs and measures of symptoms in individuals with schizophrenia will also be studied.