GABA Drugs for Cannabis-Use Disorders: Initial Mechanistic Studies in Humans

说明(申请人提供)：大麻仍然是包括美国在内的全世界最常用的非法药物。不仅有相对较大比例的人口报告使用大麻，而且与其他滥用药物一样，这些人中有相当大一部分人习惯性地使用大麻，并符合药物使用障碍的诊断标准。此外，大麻使用障碍与治疗入院和复发率相当，与其他被认为危害更大的滥用药物不相上下。尽管大麻使用造成了重大的公共卫生问题，但明确侧重于确定和开发治疗大麻使用障碍的药物的临床前或临床研究有限。来自临床前和临床研究的数据表明，激动剂替代治疗是管理药物使用障碍的有效手段，这一策略也适用于大麻使用障碍。这里提出的实验代表了评估GABA能药物作为潜在的“激动剂”药物治疗大麻使用障碍的第一步。GABA之所以成为靶子，是因为大麻素和作用于中枢GABA能系统的药物产生的影响有很大重叠，神经解剖学、神经化学和行为研究支持大麻素和GABA能系统之间的功能联系。这些研究将测试选择性GABA再摄取抑制剂替加宾、GABAA正向调节剂地西潘和GABAB激动剂巴氯芬增强9-THC的行为和生理效应的能力，从而检验具有不同作用机制的GABA能药物的“激动剂”特征。这些实验的主要结果是9-THC产生的内感线索。？9-THC的相互感觉效应将通过药物识别程序来测量，这是一种表征药物和药物相互作用的药理学特异性和灵敏的手段。此外，主观效果问卷、精神运动表现和记忆任务以及心血管和体温生理测量将被包括在内，以更全面地评估？9-THC单独和与GABA能化合物一起使用的效果。这里提出的实验是新颖和创新的，因为很少有人体研究测试GABA能药物对大麻素的影响。此外，这些研究之所以重要，至少有三个原因。首先，也许最重要的是，拟议实验产生的数据将为今后旨在开发大麻使用障碍的GABA能治疗方法的研究提供方向和基础。其次，这些数据将通过研究大麻素和GABA能系统之间的相互作用，提供关于大麻素对人类影响的神经生物学方面的有价值的信息。最后，这些实验将提供关于评估CB-GABA相互作用的临床前研究结果推广到人类的程度的翻译信息。与公共卫生相关：大麻是美国最常用的非法药物，其使用与滥用和依赖的发展速度、接受治疗和复发有关，与被误解为危害更大的其他非法药物相当。目前还没有对大麻使用障碍进行有效的药物治疗。本实验是通过研究GABA再摄取抑制剂替加宾、GABAA正性调节剂地西潘和GABAB激动剂巴氯芬与β9-THC之间的相互作用来评价GABA能药物作为潜在药物治疗的初步步骤。

DESCRIPTION (provided by applicant): Cannabis remains the most commonly used illicit drug worldwide, including the United States. Not only does a relatively large percentage of the population report using cannabis, but like other drugs of abuse, a significant proportion of those persons use it habitually and meet diagnostic criteria for drug-use disorders. Moreover, cannabis-use disorders are associated with treatment admission and relapse rates comparable to other drugs of abuse perceived as more harmful. Despite the significant public health concern posed by cannabis use, there has been limited preclinical or clinical research that has focused explicitly on the identification and development of medications to treat cannabis-use disorders. Data from preclinical and clinical research suggest that agonist replacement treatment is an effective means to manage drug-use disorders, and that this strategy would be viable for cannabis-use disorders as well. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential "agonist-like" pharmacotherapies for cannabis-use disorders. GABA is being targeted because there is substantial overlap in the effects produced by cannabinoids and drugs acting at central GABAergic systems, and neuroanatomical, neurochemical and behavioral studies support a functional link between cannabinoid and GABAergic systems. The studies proposed here will test the ability of the selective GABA reuptake inhibitor tiagabine, the GABAA positive modulator diazepam and the GABAB agonist baclofen to enhance the behavioral and physiological effects of ?9-THC, thus examining the "agonist-like" profile of GABAergic drugs with varying mechanisms of action. The primary outcome for these experiments is the interoceptive cue produced by ?9-THC. The interoceptive effects of ?9-THC will be measured using the drug-discrimination procedure, which is a pharmacologically specific and sensitive means to characterize drugs and drug interactions. In addition, subjective effects questionnaires, psychomotor performance and memory tasks, and cardiovascular and thermal measures of physiology will be included to more fully assess the effects of ?9-THC alone and in combination with GABAergic compounds. The experiments proposed here are novel and innovative because there are very few studies in humans to have tested the effects of GABAergic drugs on cannabinoids. In addition, these studies are important for at least three reasons. First, and perhaps most importantly, the data generated from the proposed experiments will provide the direction and foundation for future studies aimed at the development of GABAergic treatments for cannabis-use disorders. Second, these data will provide valuable information regarding the neurobiology of the effects of cannabinoids in humans by examining the interactions between cannabinoid and GABAergic systems. Finally, these experiments will provide translational information regarding the extent to which the results from preclinical studies that have evaluated CB-GABA interactions generalize to humans. Public Health Relevance: Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence, treatment admission and relapse that are comparable to other illicit drugs that are misperceived as more harmful. Currently there is no effective pharmacological treatment for cannabis-use disorders. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential pharmacotherapies by characterizing interactions between ?9-THC and the selective GABA reuptake inhibitor tiagabine, the GABAA positive modulator diazepam and the GABAB agonist baclofen.