Development of a rat model of cannabis smoke self-administration

 描述(申请人提供)：大麻是美国使用最广泛的非法药物，每年有100多万人因大麻依赖而接受治疗。鉴于长期使用大麻可能造成依赖和有害影响，迫切需要更好地了解支持使用大麻的机制，以便开发减少这种使用的治疗方法。有几种动物模型已经证明了可靠的静脉注射大麻素类药物，如Δ9THC(THC)。然而，大多数人类的使用是通过吸入大麻烟雾发生的，除了THC外，大麻烟雾中还含有许多大麻类化合物，其中一些具有精神活性，可能与THC相互作用以改变其增强效果。因此，使用大麻烟雾自主给药的动物模型将更接近人类实际使用的条件，并将开辟大麻使用和滥用研究的新方向。这项研究计划的长期目标是使用啮齿动物模型来研究吸烟大麻的强化作用，最终目标是开发减少大麻使用/滥用的疗法。作为实现这一目标的第一步，CEBRA R21项目的目标是开发和验证一种系统，通过该系统，老鼠可以自我管理大麻烟雾。据我们所知，没有关于啮齿动物自主吸食吸食滥用药物的报告；然而，在灵长类动物中，已经有几次示范表明，包括可卡因和海洛因在内的吸食滥用吸食药物的自我吸食是可靠的。此外，我们有初步数据表明，被动吸食大麻后大鼠出现依赖，证明了大麻烟雾作为药物输送工具在该物种中的有效性。根据这些公布的和初步的数据，我们的中心假设是，大鼠会自我吸入大麻，而且 吸烟的自我给药行为将类似于报告的静脉注射大麻类药物和其他药物的滥用。我们已经设计了一种装置，可以使用与其他滥用药物类似的实验设计，精确校准、根据反应传递大麻烟雾。我们将使用这个装置来确定大鼠是否会可靠地对大麻烟雾传递表现出操作性反应，以及这种反应是否对烟雾THC含量和CB1受体激活以及预测烟雾传递的线索敏感。我们还制定了多种策略，以增加获得自我管理行为的可能性。成功开发了啮齿动物大麻烟雾自我给药模型，将为更大规模的大麻吸烟神经行为机制研究计划奠定基础。此外，这一模式还可适用于其他吸食滥用药物(如烟草)。

 DESCRIPTION (provided by applicant):: Cannabis is the most widely-used illicit drug in the U.S., and over 1 million people are treated for cannabis dependence annually. Given the potential for dependence as well as deleterious effects of chronic use, there is an urgent need to better understand the mechanisms supporting cannabis use, in order to develop therapies to reduce such use. There are several animal models in which reliable intravenous self-administration of cannabinoids such as Δ9THC (THC) has been demonstrated. Most human use, however, occurs through inhalation of cannabis smoke, which contains numerous cannabinoids aside from THC, some of which is psychoactive and may interact with THC to alter its reinforcing effects. Hence, an animal model that employs cannabis smoke self-administration would more closely mimic the conditions of actual human use, and would open new directions of research on cannabis use and abuse. The long-term goal of this research program is to use rodent models to investigate the reinforcing effects of smoked cannabis, with the ultimate goal of developing therapies for reducing cannabis use/abuse. As the first step toward this goal, the objective of this CEBRA R21 project is to develop and validate a system by which rats can self-administer cannabis smoke. To our knowledge, there are no reports of self-administration of smoked drugs of abuse in rodents; however, there have been several demonstrations in primates of reliable self-administration of smoked drugs of abuse, including cocaine and heroin. In addition, we have preliminary data showing development of dependence following passive cannabis smoke administration in rats, demonstrating the efficacy of cannabis smoke as a drug delivery vehicle in this species. On the basis of these published and preliminary data, our central hypothesis is that rats will self-administer cannabis smoke, and that smoke self-administration behavior will be similar to that reported for intravenous cannabinoids and other drugs of abuse. We have designed an apparatus that will allow precisely-calibrated, response-contingent delivery of cannabis smoke using experimental designs similar to those employed with other drugs of abuse. We will use this apparatus to determine whether rats will reliably show operant responding for cannabis smoke delivery, and whether this responding is sensitive to smoke THC content and CB1 receptor activation, as well as to cues predictive of smoke delivery. We have also developed multiple strategies to increase the likelihood of obtaining self-administration behavior. Successful development of a rodent cannabis smoke self-administration model will lay the groundwork for a larger research program on neurobehavioral mechanisms of cannabis smoking. In addition, this model could be adapted for use with other smoked drugs of abuse (e.g., tobacco).