Imaging Brain Cannabinoid Receptors in Cannabis Dependence, Withdrawal and Abstin

描述(申请人提供)：大麻是世界上最常用的非法药物。人们越来越多地认识到大麻依赖综合征包括耐受和戒断。此外，大麻使用率在青春期早期增加，此时发育中的大脑可能特别容易受到环境暴露的影响。过去几十年来，大麻的效力似乎有所增加，这进一步加剧了人们对公共卫生的担忧。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对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)产生精神活性效应。反复接触大麻和CB1R激动剂与耐受性和依赖性的形成有关。虽然这已经被证明伴随着CB1R在动物中的下调，但它还没有在人类体内得到证实。在人类和动物中停止长期大量接触大麻类药物，以及对依赖大麻类药物的动物使用CB1R拮抗剂，与明显的戒断综合征有关。最后，随着长时间的禁欲，耐受性似乎发生了逆转，在动物中，这已被证明伴随着CB1R的正常化。然而，这一点尚未在人类身上得到证实，无论是在死后还是在体内。目前这项建议的目的是使用经过验证的CB1R PET配体[11C]Omar和高分辨率研究断层扫描(HRRT)来衡量大麻依赖者在1)基线、2)短暂(48小时)确诊住院戒断(大麻戒断和CB1R下调的高峰)和3)长期(4周)确诊门诊戒断后CB1R的体内可获得性。预计在基线时，大麻依赖受试者(n=8)的CB1R可用性将低于匹配的对照组(n=8)，但在戒断4周后，这种差异将不再存在。此外，与其基线状态相比，大麻依赖受试者在急性大麻戒断期间CB1R的可获得性更低。综上所述，这项研究的数据有望阐明长期吸食大麻的神经生物学后果及其对CB1受体的影响，并将为了解CB1受体在积极使用大麻和戒断过程中的地位和功能提供新的线索。

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.