Development of a rat model of cannabis smoke self-administration

大麻烟雾自我管理大鼠模型的开发

• 批准号: 8915392
• 负责人: ANDREW Porter MAURER
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915392
• 关键词: Address; Adverse effects; Agonist; Animal Model; Area; Behavior; Behavioral; Breathing; CNR1 gene; Cannabidiol; Cannabinoids; Cannabis; Cannabis Abuse; Chronic; Cocaine; Cues; Data; Dependence; Development; Drug Delivery Systems; Drug abuse; Experimental Designs; Exposure to; Foundations; Goals; Gold; Heroin; High Prevalence; Hormonal; Human; Illicit Drugs; Impaired cognition; Intake; Intravenous; Knowledge; Learning; Marijuana Dependence; Marijuana Smoking; Mental disorders; Methods; Modeling; Monkeys; Pharmaceutical Preparations; Population; Primates; Procedures; Psychotropic Drugs; Publishing; Rattus; Receptor Activation; Reporting; Research; Risk; Rodent; Rodent Model; Self Administration; Self-Administered; Smoke; Smoking; System; Tobacco; United States Substance Abuse and Mental Health Services Administration; Withdrawal Symptom; Work; addiction; base; cannabinoid receptor; design; drug of abuse; experience; innovation; intravenous administration; marijuana use; marijuana user; neurobehavioral; novel; olfactory stimulus; programs; public health relevance; relating to nervous system; research study; response; smoke inhalation; success; synthetic cannabinoid; therapy development

 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).

 大麻是美国使用最广泛的非法药物，每年有100多万人因大麻依赖接受治疗。鉴于长期使用大麻可能产生依赖性和有害影响，迫切需要更好地了解支持大麻使用的机制，以便开发减少这种使用的疗法。有几种动物模型，其中已经证明了大麻素如Δ 9 THC（THC）的可靠静脉内自我给药。然而，大多数人类使用是通过吸入大麻烟雾发生的，大麻烟雾中含有除THC外的许多大麻素，其中一些是精神活性的，可能与THC相互作用以改变其增强效果。因此，采用大麻烟自我给药的动物模型将更接近于模拟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食大麻的强化作用，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个系统，通过该系统，大鼠可以自我管理大麻烟雾。据我们所知，目前还没有啮齿类动物自我施用吸烟药物的报告;然而，灵长类动物中已经有几次证明了吸烟药物滥用（包括可卡因和海洛因）的可靠自我施用。此外，我们有初步数据显示，大鼠被动给予大麻烟后产生了依赖性，证明了大麻烟作为该物种的药物递送载体的功效。根据这些已发表的初步数据，我们的核心假设是，大鼠会自我吸食大麻烟， 吸烟者自我给药行为将类似于所报道的静脉内大麻素和其他滥用药物的行为。我们设计了一种装置，它将允许精确校准，响应视情况提供大麻烟雾使用类似于那些与其他药物滥用的实验设计。我们将使用该装置来确定大鼠是否会可靠地显示大麻烟雾递送的操作性响应，以及这种响应是否对烟雾THC含量和CB 1受体激活敏感，以及对烟雾递送的预测线索敏感。我们还开发了多种策略来增加获得自我管理行为的可能性。啮齿动物大麻烟自我管理模型的成功开发将为大麻吸烟神经行为机制的更大研究计划奠定基础。此外，该模型可适用于其他吸烟滥用药物（例如，烟草）。