Comparative Pharmacology of Cannabinoids in Rodent Models

项目摘要 Cannabis sativa/indica（大麻植物）是美国最常滥用的物质，但 根据联邦法律持有仍属非法精神活性植物大麻素，如Δ9- 四氢大麻酚（tetrahydrocannabinol，THC）通过激活CB 1和CB 2而对生理和行为产生影响 受体。这些受体是内源性大麻素系统的一部分，内源性大麻素系统是体内的几种脂质信号系统之一。 大脑/身体发现这些大麻素作用的潜在机制并表征其作用 对生理和行为的影响，部分是由于在动物身上进行的研究，特别是在啮齿动物身上 模型该领域的未来进展还将涉及使用这些模型得出的发现。因此，我们认为， 对这些模式的优点和局限性的基本了解至关重要。最近，我们发现了一个 在大鼠和小鼠中THC的影响中有趣的物种X性别相互作用。简单地说，大鼠表现出明显的性别 THC注射后生理和行为反应的差异，而雌性和雄性小鼠 也有类似的反应。拟议项目的总体目标是调查可能 这些差异的基础，并确定在何种程度上类似的配置文件特点THC的影响， 生理和行为。并行比较生理（温度和心脏）和 肺功能）和行为（辨别刺激）的影响，THC和大麻提取物将 在雌性和雄性大鼠和小鼠中。药代动力学和受体机制的差异将在 在啮齿类动物研究中，在胃肠外注射给药途径后和给药后， 通过与预防更相关的吸入和口服给药途径。这些研究的结果将 为研究大麻潜在机制的啮齿动物模型的选择提供了经验基础 使用.

PROJECT SUMMARY Cannabis sativa/indica (marijuana plant) is the most commonly abused substance in the United States, but is still classified as illegal to possess under federal law. Psychoactive phytocannabinoids such as Δ9- tetrahydrocannabinol (THC) produce their effects on physiology and behavior through activation of CB1 and CB2 receptors. These receptors are part of the endocannabinoid system, one of several lipid signaling systems in the brain/body. Discovery of these mechanisms underlying cannabinoid action and characterization of their effects on physiology and behavior were due, in part, to research conducted in animals, and specifically, in rodent models. Future progress in this area also will involve findings derived from work with these models. Hence, fundamental knowledge of the advantages and limits of the models are crucial. Recently, we discovered an intriguing species X sex interaction in the effects of THC in rats and mice. Briefly, rats exhibited pronounced sex differences in physiological and behavioral responses following THC injection whereas female and male mice showed similar responses. The overall goals of the proposed project are to investigate mechanisms that may underlie these differences and to determine the extent to which a similar profile characterizes THC’s effects on physiology and behavior. Side-by-side comparisons of the physiological (temperature and cardiac and pulmonary function) and behavioral (discriminative stimulus) effects of THC and cannabis extracts will be made in female and male rats and mice. Differences in pharmacokinetics and receptor mechanisms will be characterized following parenteral injection routes of administration for rodent studies and after administration via more translationally relevant inhalational and oral routes of administration. The results of these studies will provide an empirical basis for choice of rodent model with which to investigate mechanisms underlying cannabis use.