Citicoline-Induced Modulation of Cannabis Effects: Imaging & Mechanism of Action

描述（由申请人提供）：大麻是美国最常见的滥用非法药物，但没有治疗其滥用或依赖。由于其与药物滥用门户理论的已知联系，NIDA是一个重大的公共卫生问题，过去几年NIDA的使命一直旨在确定治疗大麻滥用和依赖的安全有效的候选疗法，特别是那些可以给弱势群体的疗法。本提案的总体目标是测试天然脑化学物质胞苷-5 '-二磷酸胆碱（胞磷胆碱）的营养补充剂对大麻引起的中毒和滥用模式的影响。这种补充剂最近被证明可以减少大麻在RFA-DA-04-014（大麻相关疾病的药物开发）下授予的开放标签试验中的使用。由于胞磷胆碱是哺乳动物大脑中的天然化学物质，因此相对安全，在治疗中风和其他神经系统疾病方面非常有用。目前还不清楚大麻是如何影响大脑功能的，无论是急性还是慢性使用，因此拟议的研究旨在收集数据，作为探索治疗大麻滥用新策略的基础。这些目标将通过使用脑成像技术，如脑电图，磁共振成像来实现，并将进行研究，以确定胞磷胆碱对大麻使用及其致醉作用的作用机制。作为设计治疗大麻依赖药物的第一步，我们建议在自然环境中对胞磷胆碱对大麻使用模式进行双盲、安慰剂对照评估。然后，我们将使用BOLD信号检测记录急性施用大麻对局部脑血流量的影响。最后，我们将研究胞磷胆碱是否改变大麻诱导的线索诱导的渴望。总的来说，这些研究应该产生关于补充天然大脑化学物质如何改变大麻效果的重要信息，从而减少其使用。本系列研究的结果可能对大麻依赖的药物治疗以及与长期使用相关的神经生物学损伤的初级和二级预防具有重要意义。此外，拟议项目的结果可以提供重要的见解的病理生理学和过程中的大麻依赖（和潜在的其他药物依赖性疾病）。最后，鉴于胞磷胆碱没有任何副作用，这些结果也可能为扩大孕妇、药物依赖母亲所生子女和青少年等弱势群体相对有限的治疗选择提供重要线索。公共卫生相关性：大麻是美国最常滥用的非法药物，但对其滥用或依赖没有治疗方法。胞磷胆碱，一种大脑中天然存在的化学物质，在一项试点临床试验中被证明可以减少大麻的使用。利用磁共振脑成像和脑电图技术，这项应用将探索大麻依赖的作用机制，并开发新的治疗策略。

DESCRIPTION (provided by applicant): Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. As a significant public health problem because of its known association with the Gateway theory of drug abuse, NIDA's mission over the past few years has been aimed at identifying safe and effective candidate therapies for marihuana abuse and dependence, particularly those that can be given to vulnerable populations. The overall objectives of this proposal are to test a nutritional supplement of the natural brain chemical, cytidine-5'-diphosphate choline (citicoline) for its effects on marihuana-induced intoxication and abuse patterns. This supplement was recently shown to reduce marihuana use in an open label trial of a grant that was awarded under RFA-DA-04-014 (Medication Development for Cannabis-Related Disorders). Because citicoline is a natural chemical in mammalian brain, it is relatively safe and has been very useful in treating stroke and other neurological disorders. It is still unclear how marihuana affects brain function, either acutely or after chronic use, so the proposed studies are designed to collect data that will serve as a foundation for exploring new strategies for treating marihuana abuse. These goals will be accomplished by using brain imaging techniques such as electroencephalography, magnetic resonance imaging and studies will be conducted to identify the mechanism of action of citicoline's effects on marihuana use and its intoxicating effects. As a first step in devising a medication to treat marihuana dependence we propose to conduct a double-blind, placebo-controlled assessment of citicoline on marihuana use patterns in a natural setting. We will then document the effects of acutely administered marihuana on regional cerebral blood flow using BOLD signal detection. Finally, we will study whether citicoline alters marihuana-induced cue-induced craving. Collectively, these studies should yield important information on how supplementation with a natural brain chemical alters marihuana's effects such that its use is decreased. The results of the present series of studies could have important implications for the pharmacotherapy of marihuana dependence as well as primary and secondary prevention of the neurobiological damage associated with chronic use. Furthermore, the outcome of the proposed project could offer important insights into the pathophysiology and course of marihuana dependence (and potentially on other drug dependence disorders). Lastly, given the lack of any side effects of citicoline, these results also may provide important leads for expanding the relatively limited treatment options for vulnerable populations such as pregnant women, children born to drug-dependent mothers and adolescents. PUBLIC HEALTH RELEVANCE: Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. Citicoline, a naturally occurring chemical in the brain, has been shown to reduce marihuana use in a pilot clinical trial. Using magnetic resonance brain imaging and EEG techniques, this application will explore the mechanism of action and develop new treatment strategies for marihuana dependence.