Imaging Brain Cannabinoid Receptors in Cannabis Dependence, Withdrawal and Abstin

对大麻依赖、戒断和戒断中的大脑大麻素受体进行成像

• 批准号: 8191449
• 负责人: DEEPAK Cyril D'SOUZA
• 金额: $ 24.83万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191449
• 关键词: Abstinence; Accident and Emergency department; Acute; Address; Admission activity; Age; Agonist; Animals; Applications Grants; Binding; Biological Assay; Brain; Brain imaging; CNR1 gene; Cannabinoids; Cannabis; Chronic; Consumption; Data; Dependence; Development; Disease; Down-Regulation; Environmental Exposure; Exposure to; Gender; Hospitals; Hour; Human; Illicit Drugs; Image; Individual; Inpatients; Kinetics; Knowledge; Label; Laboratories; Ligands; Light; Literature; Marijuana Dependence; Measurement; Measures; Methods; Monkeys; Neurobiology; Outpatients; Participant; Patient Self-Report; Peripheral; Positron-Emission Tomography; Public Health; Recording of previous events; Recovery; Recruitment Activity; Relative (related person); Reproducibility; Research; Resolution; Scanning; Signal Transduction; Study Section; Substance Withdrawal Syndrome; Syndrome; System; Testing; Tetrahydrocannabinol; Time; Withdrawal; cannabinoid receptor; desensitization; early adolescence; in vivo; innovation; radiotracer; receptor; receptor downregulation; receptor function; tomography

DESCRIPTION (provided by applicant): Cannabis is the most commonly used illicit drug worldwide. There is increasing recognition of a cannabis dependence syndrome that includes both tolerance and withdrawal. Furthermore, the rates of cannabis use have increased during early adolescence, when the developing brain might be especially susceptible to environmental exposures. This public health concern is further fueled by the fact that the potency of cannabis seems to have increased over the past decades. There is also increasing demand for treatments for cannabis use disorders. Therefore, it is important to fully understand the consequences of cannabis dependence in humans on the brain cannabinoid system. Exogenous cannabinoids produce their psychoactive effects via the activation of brain CB1 receptors (CB1R). Repeated exposure to cannabis and CB1R agonists is associated with the development of tolerance and dependence. While this has been shown to be accompanied by CB1R downregulation in animals, it has yet to be demonstrated in humans, in vivo. The discontinuation of chronic, heavy exposure to cannabinoids in both humans and animals, and the administration of CB1R antagonists to cannabinoid dependent animals, is associated with a clear withdrawal syndrome. Finally, with prolonged abstinence there seems to be a reversal of tolerance, which in animals has been shown to be accompanied by normalization of CB1Rs. However, this has yet to be demonstrated in humans, either post mortem or in vivo. The aim of the current proposal is to use the validated CB1R PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT) to measure CB1R availability in vivo in cannabis-dependent individuals at 1) baseline, 2) following brief (48 hours) confirmed inpatient abstinence (at the peak of cannabis withdrawal and CB1R downregulation), and 3) after prolonged (4 weeks) confirmed outpatient abstinence. It is expected that at baseline, cannabis-dependent subjects (n=8) will have lower CB1R availability than matched controls (n=8), but this difference will no longer be present after 4 weeks of abstinence. Furthermore, cannabis-dependent subjects will have lower CB1R availability during acute cannabis withdrawal relative to their baseline state. Taken together, it is hoped that data from this study will elucidate the neurobiological consequences of chronic cannabis consumption and its effect on CB1 receptors, and will shed new light on the status and function of CB1 receptors during active cannabis use, and withdrawal. PUBLIC HEALTH RELEVANCE: Little is known about the consequences of heavy cannabis use on the brain cannabinoid system. This grant application proposes to use brain imaging to study the changes in the brain cannabinoid receptor system as a result of heavy cannabis use, 2 days after stopping cannabis use and again after 4 weeks of abstinence from cannabis.

描述（由申请人提供）：大麻是全球最常用的非法药物。对大麻依赖综合征的认识越来越多，包括公差和戒断。此外，当发育中的大脑可能特别容易受到环境暴露时，大麻的使用率也有所提高。在过去的几十年中，大麻的效力似乎有所提高，这一事实进一步加剧了这种公共卫生的关注。对大麻使用障碍的治疗需求也不断增加。因此，重要的是要充分了解人类对脑大麻素系统中大麻依赖的后果。外源性大麻素通过脑CB1受体（CB1R）的激活产生其精神活性作用。反复接触大麻和CB1R激动剂与耐受性和依赖性的发展有关。尽管已证明这伴随着动物的CB1R下调，但在人类的体内尚未证明它。人类和动物中慢性大麻素的慢性暴露以及CB1R拮抗剂对大麻素依赖性动物的终止，与明显的戒断综合征有关。最后，随着节制的延长，似乎有一种耐受性的逆转，在动物中已显示出伴随CB1RS的归一化。但是，这尚未在人类中，无论是在验尸还是体内证明。 The aim of the current proposal is to use the validated CB1R PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT) to measure CB1R availability in vivo in cannabis-dependent individuals at 1) baseline, 2) following brief (48 hours) confirmed inpatient abstinence (at the peak of cannabis withdrawal and CB1R downregulation), and 3) after prolonged (4 weeks) confirmed门诊禁欲。预计在基线时，大麻依赖的受试者（n = 8）的CB1R可用性将比匹配的对照（n = 8）低，但是在禁欲4周后，这种差异将不再存在。此外，相对于基线状态，在急性大麻撤离期间，依赖大麻的受试者的CB1R可用性较低。综上所述，希望这项研究的数据能够阐明慢性大麻消耗及其对CB1受体的影响的神经生物学后果，并将为活跃的大麻使用和戒断期间CB1受体的状态和功能提供新的启示。 公共卫生相关性：对大麻使用对脑大麻素系统的后果知之甚少。该赠款的应用建议使用脑成像来研究大麻使用大麻的大麻使用的结果，在停止大麻使用后2天，在对大麻戒酒的4周后再次。