Imaging Brain Cannabinoid Receptors in Cannabis Dependence, Withdrawal and Abstin

描述（由申请人提供）：大麻是世界上最常用的非法药物。人们日益认识到大麻依赖综合症包括耐受和戒断。此外，大麻的使用率在青春期早期有所增加，此时发育中的大脑可能特别容易受到环境暴露的影响。这种公共卫生问题进一步加剧了大麻的效力在过去几十年中似乎有所增加的事实。对大麻使用障碍治疗的需求也在增加。因此，重要的是要充分了解人类大麻依赖对大脑大麻素系统的影响。外源性大麻素通过激活脑CB1受体（CB1R）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。虽然这已被证明伴随着CB1R在动物中的下调，但它尚未在人体内得到证实。在人类和动物中停止长期、大量暴露于大麻素，以及向大麻素依赖动物施用CB1R拮抗剂，与明显的戒断综合征相关。最后，随着长期禁欲，耐受性似乎出现逆转，在动物中，这已被证明伴随着CB1R的正常化。然而，这还没有在人类中得到证实，无论是死后还是体内。 当前提案的目的是使用经验证的CB1R PET配体[11 C]OMAR和高分辨率研究断层扫描（HRRT）在1）基线，2）短暂（48小时）确认住院戒断（大麻戒断和CB1R下调的高峰）后，以及3）长期（4周）确认门诊戒断后，测量大麻依赖个体的CB1R体内可用性。预计在基线时，大麻依赖受试者（n=8）的CB1R可用性低于匹配的对照组（n=8），但在戒断4周后，这种差异将不再存在。此外，大麻依赖受试者在急性大麻戒断期间的CB1R可用性相对于其基线状态较低。总的来说，希望这项研究的数据将阐明慢性大麻消费的神经生物学后果及其对CB1受体的影响，并将为主动使用大麻和戒断期间CB1受体的状态和功能提供新的线索。 公共卫生相关性：人们对大量使用大麻对大脑大麻素系统的影响知之甚少。这项拨款申请建议使用大脑成像来研究大脑大麻素受体系统的变化，这些变化是由于大量使用大麻，停止使用大麻后2天以及大麻戒断4周后的结果。

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.