Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence

描述（由申请人提供）：大麻使用障碍是一个重大的公共卫生问题，缺乏有效的药物是需要克服的一个关键障碍。该应用基于来自我们实验室的有希望的结果，该结果表明作用于包含电压依赖性钙通道（VDCC）的a2 d-1亚基和/或升高g-氨基丁酸（即，GABA）将是大麻使用障碍的有效药物。我们的实验室结果得到了最近一项试点临床试验的支持，该试验表明， 一种VDCC配体，并提高GABA，减少依赖性，寻求治疗的成年人的大麻使用。本提案的目标是建立在这些有前途的实验室和临床研究结果的基础上，通过确定门诊维持普瑞巴林（“下一代”VDCC配体）和噻加宾（GABA再摄取抑制剂）的能力，以减弱大麻的强化作用。将对普瑞巴林进行检测，因为尽管它们的作用机制相同，但与加巴喷丁相比，普瑞巴林的药代动力学特征有所改善，临床结果表明这转化为更大的药理学有效性。将测试噻加宾，因为其作用与加巴喷丁和普瑞巴林重叠，GABA升高是加巴喷丁对大麻使用的影响的可能机制，我们最近的数据表明，当与D9-THC组合测试时，噻加宾产生的作用与加巴喷丁相当。将对门诊患者维持给药进行检测，因为其更接近临床治疗情况。大麻自我管理使用的同时进行的比例药物金钱选择程序将是主要的结果，因为药物寻求和吸毒行为，以及选择使用药物排除其他行为，是药物依赖的定义特征，药物自我管理程序是治疗效果的预测。在药物维持期间，还将监测自然环境中的大麻使用情况，作为优化资源管理和加快干预措施制定步伐的次要成果。我们的初步数据与拟议的程序支持该项目的可行性，组装的研究团队是高素质的，环境将大大有助于研究的成功。拟议的项目是创新的，因为它采用了一种新的混合程序来研究药物维持对实验室中直接大麻效应以及自然环境中大麻使用的影响，普瑞巴林和噻加宾对大麻自我管理的影响以前没有进行过测试，并且将实施一种新的实时药物维持合规技术。积极的发现将通过快速推进目前可用于治疗大麻使用障碍的药物，促进进一步药物开发的新药理学靶点，并提供有关大麻强化机制的宝贵基础科学信息，产生直接和持续的影响。

DESCRIPTION (provided by applicant): Cannabis use disorders are a significant public health concern and the absence of effective medications is a critical barrier to overcome. This application is founded on promising results from our laboratory suggesting that drugs that act at a2d-1 subunit containing voltage-dependent calcium channels (VDCCs) and/or elevate g- aminobutyric acid (i.e., GABA) will be effective medications for cannabis-use disorders. Our laboratory results are supported by a recent pilot clinical trial showing that gabapentin, which is a VDCC ligand and elevates GABA, reduced cannabis use in dependent, treatment-seeking adults. The goal of the present proposal is to build upon these promising laboratory and clinical findings by determining the ability of outpatient maintenance on pregabalin, a "next generation" VDCC ligand, and tiagabine, a GABA reuptake inhibitor, to attenuate the reinforcing effects of cannabis. Pregabalin will be tested because, although their mechanism of action is the same, the pharmacokinetic profile of pregabalin is improved compared to gabapentin, and clinical results suggest that this translates into greater pharmacotherapeutic effectiveness. Tiagabine will be tested because its effects overlap with gabapentin and pregabalin, GABA elevation is a possible mechanism for gabapentin's effects on cannabis use, and our recent data demonstrated that tiagabine produced a profile of effects that was comparable to gabapentin when tested in combination with D9-THC. Outpatient maintenance dosing will be tested because it more closely resembles the clinical treatment situation. Cannabis self-administration using a concurrent progressive-ratio drug-money choice procedure will be the primary outcome because drug seeking and drug taking behaviors, and the choice to use drugs to the exclusion of other behaviors, are defining characteristics of drug dependence, and drug self-administration procedures are predictive of therapeutic efficacy. Cannabis use in the natural environment will also be monitored during drug maintenance as a secondary outcome to optimize resource management and quicken the pace of intervention development. Our preliminary data with the proposed procedures support the feasibility of the project, the assembled research team is highly qualified and the environment will significantly contribute to the success of the research. The proposed project is innovative because it employs a novel hybrid procedure to study the impact of medication maintenance on direct cannabis effects in the laboratory as well as cannabis use in the natural environment, the effects of pregabalin and tiagabine on cannabis self-administration have not been tested previously, and a novel, real-time medication maintenance compliance technology will be implemented. Positive findings will exert an immediate and sustained impact by rapidly advancing currently available medications for the treatment of cannabis-use disorders, promoting novel pharmacological targets for further medications development and providing valuable basic science information about the mechanisms underlying cannabis reinforcement.