CB1R Availability in Synthetic Psychoactive Cannabinoid Users

合成精神活性大麻素使用者中 CB1R 的可用性

• 批准号: 9244957
• 负责人: DEEPAK Cyril D'SOUZA
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244957
• 关键词: Accident and Emergency department; Acute; Address; Admission activity; Adverse event; Affect; Affinity; Age; Agonist; Animals; Automobile Driving; Behavior; Binding; Biological Markers; Brain; CNR1 gene; Cannabinoids; Cannabis; Case Study; Chronic; Clinical Laboratory Information Systems; Cognition; Data; Dependence; Down-Regulation; Electrophysiology (science); Emergency department visit; Exposure to; Forensic Medicine; Gender; Glean; Goals; Human; Individual; Kinetics; Knowledge; Label; Law Enforcement; Ligands; Literature; Long-Term Effects; Measures; Medical; Methods; Names; Pharmaceutical Preparations; Pharmacology; Platinum; Poison Control Centers; Positron-Emission Tomography; Psychotic Disorders; Reporting; Reproducibility; Research; Resolution; Seizures; Spices; Surveys; System; Testing; Tetrahydrocannabinol; Time; Time Study; adverse outcome; base; cannabinoid receptor; cognitive function; cognitive performance; cognitive testing; desensitization; endogenous cannabinoid system; high resolution imaging; illicit drug use; in vivo; indexing; information processing; marijuana user; news; performance tests; receptor; tomography

PROJECT SUMMARY Background: There is growing concern about the recreational use of synthetic psychoactive cannabinoids (SPCs) sold as `Spice'. Unlike, delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of herbal cannabis, which is a weak efficacy, low affinity, partial agonist of brain cannabinoid receptors (CB1Rs), SPCs are high efficacy, high affinity, full CB1R agonists. Consistent with this profile, while SPCs produce some effects similar to cannabis, they are generally more potent and unpredictable; in fact SPCs have been associated with catastrophic medical and psychiatric adverse outcomes. Despite concerns about the negative consequences of recreational Spice use, there is very little controlled data on the effects of acute or repeated exposure to SPCs on the brain endocannabinoid system or brain function in general. The main purpose of the proposed study, is to compare CB1R availability in Spice dependent (Spice users [SUs]), cannabis dependent (cannabis users [CUs]) and healthy controls (HCs). Furthermore, cognitive test performance will be assessed in order to relate the receptor availability to domains germane to “real world” functioning. Given the plethora of Spice products and their constituent SPCs, differences in their pharmacology, and the limited scope of an R21 application, we will need to limit the study to the most prevalent SPC around the time around the time the study is expected to be initiated. The latter will identified based on information gleaned from the National Forensic Laboratory Information System (NFLIS), local DEA office, local emergency rooms, news media, Poison Control Centers and blogs about Spice use (e.g., Drugs-Forum). Cognitive test performance will be assessed in order to relate receptor availability to “real world” functioning. Similarly, cannabinoid-sensitive electrophysiological measures of information processing (P300 and gamma driving) will relate receptor availability to proximal biomarkers of brain function. Primary Hypothesis: Spice users will show lower CB1R availability compared to CUs and HCs. Exploratory Hypotheses: Compared to CUs and HCs, SUs will show worse cognitive test performance, and cannabinoid-sensitive electrophysiological indices of information processing (P300 amplitude and gamma oscillations). Methods: Using the CB1R specific PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT), CB1R availability will be measured in SUs, CUs and HCs. Cognitive function will be assessed using the CANTAB battery. P300 and gamma oscillations will also be measured. Preliminary Results: Spice Users (n=2) show robust reductions in CB1R availability relative to cannabis users (n=11) and healthy controls (n=19). The magnitude of the differences (effects size d) between SUs vs. CUs, and HCs were -1.29 and -6, respectively. Differences between SUs and CUs were comparable in magnitude to the differences between CUs and HCs (~15%, d=1.19).

项目摘要 背景：越来越关注合成精神活性大麻素的休闲使用 （SPC）以“香料”出售。与Delta-9-四氢大麻酚（THC）不同，主要的心理活性构成 草药大麻是一种弱效率，低亲和力，脑大麻素受体（CB1RS）的部分激动剂， SPC是高效率，高亲和力，完整的CB1R激动剂。与此配置文件一致，而SPC会产生一些 与大麻类似的作用，它们通常具有更大的潜力和不可预测的作用。实际上SPC已经 与灾难性的医学和精神病性不良后果有关。尽管担心负面 娱乐香料使用的后果，关于急性或重复的影响的受控数据很少 一般而言，在大脑内源性大麻素系统或大脑功能上接触SPC。主要目的 拟议的研究是为了比较香料依赖的CB1R可用性（香料用户[SUS]），大麻依赖性 （大麻使用者[CUS]）和健康对照（HCS）。此外，将评估认知测试表现 为了将受体的可用性与域的域与“现实世界”的功能联系起来。鉴于大量 香料产品及其成分SPC，药理学的差异以及R21的有限范围 应用，我们将需要将研究限制为研究左右的最普遍的SPC 预计将启动。后来将根据来自国家法医收集的信息来确定 实验室信息系统（NFLIS），当地DEA办公室，当地急诊室，新闻媒体，毒药控制 有关香料使用的中心和博客（例如，药物 - 毒品）。认知测试表现将按顺序进行评估 将受体的可用性与“现实世界”的功能联系起来。同样，大麻素敏感的电生理学 信息处理的度量（P300和GAMMA驾驶）将将受体的供应与近端相关联 大脑功能的生物标志物。 主要假设：与CUS和HCS相比，香料用户的CB1R可用性较低。 探索性假设：与CUS和HCS相比，SUS将显示出较差的认知测试表现，并且 信息处理的大麻素敏感电生理指标（P300放大器和伽玛 振荡）。 方法：使用CB1R特异性PET配体[11C] OMAR和高分辨率研究断层扫描 （HRRT），CB1R的可用性将在SUS，CUS和HCS中测量。认知功能将使用 Cantab电池。还将测量P300和伽马振荡。 初步结果：香料用户（n = 2）相对于大麻用户，CB1R的可用性显示出强大的减少 （n = 11）和健康对照（n = 19）。 SUS与CUS之间的差异（效应大小D）的大小， HC和HC分别为-1.29和-6。 SUS和CUS之间的差异与 CUS和HCS之间的差异（〜15％，d = 1.19）。