Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence

说明(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。这一应用是建立在我们实验室令人振奋的结果基础上的，该结果表明，作用于包含电压依赖钙通道(VDCC)和/或升高g-氨基丁酸(即GABA)的2d-1亚单位的药物将是治疗大麻使用障碍的有效药物。我们的实验室结果得到了最近的一项试点临床试验的支持，该试验表明加巴喷丁，即 VDCC配体和提高GABA，减少依赖，寻求治疗的成年人的大麻使用。本提案的目的是在这些有希望的实验室和临床发现的基础上，确定门诊维持普瑞巴林和替加宾的能力，以减弱大麻的强化作用。普瑞巴林是一种“下一代”VDCC配体，而替加宾是一种GABA再摄取抑制剂。将对普瑞巴林进行测试，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，这将转化为更好的药物治疗效果。蒂加宾将接受测试，因为它的作用与加巴喷丁和普瑞巴林重叠，GABA升高是加巴喷丁影响大麻使用的一个可能机制，我们最近的数据表明，当与D9-THC联合测试时，硫加巴滨产生的效果与加巴喷丁相当。门诊维持剂量将进行测试，因为它更接近临床治疗情况。使用同时累进比例的药物-金钱选择程序的大麻自我给药将是主要结果，因为寻求和吸毒行为以及选择使用药物而不使用其他行为是药物依赖的定义特征，药物自我给药程序是治疗效果的预测。在药物维护期间，还将监测自然环境中的大麻使用情况，作为一项次要成果，以优化资源管理，加快干预措施开发的步伐。我们的初步数据和建议的程序支持该项目的可行性，聚集的研究团队非常合格，环境将对研究的成功做出重大贡献。拟议的项目具有创新性，因为它采用了一种新的混合程序来研究药物维护对实验室中的大麻直接影响以及在自然环境中使用大麻的影响，以前从未测试过普瑞巴林和替加巴滨对大麻自我管理的影响，并将实施一种新的实时药物维护遵从性技术。积极的发现将产生直接和持续的影响，因为它将迅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目标，并提供关于大麻强化机制的宝贵基础科学信息。

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.