Cannabinoid Dependence Resubmission

描述（由申请人提供）：大麻是美国最常用的非法药物，高效合成大麻素（CB）药物JWH-018和JWH 073（以“Spice”和“K2”销售）作为普遍滥用的药物的出现表明CB滥用相关疾病构成的公共卫生挑战的严重性。大麻依赖是继尼古丁和酒精之后第三大最普遍的物质滥用障碍，30- 70%的慢性大麻吸烟者会出现CB戒断症状。尽管如此，相对较少的研究已经检查了长期施用CB在动物中的影响。为了解决这个关键的差距，我们建议开发强大的CB依赖动物模型，可用于更好地了解CB依赖的药理学和行为方面。在动物中建立CB依赖性模型的一个障碍是未能观察到明显的自发戒断综合征;症状通常是轻微的，并在几天内出现。CB拮抗剂，利莫那班，已被用来沉淀'退出'，但它仍然不清楚是否利莫那班的影响反映身体依赖性或其他内在的利莫那班的影响的表达。在每天注射高效CB 1激动剂AM 2389的小鼠的初步研究中，我们发现利莫那班增加了爪震颤并破坏了其他行为;重要的是，当每天中断激动剂注射24-72小时时，获得了定性相似的结果。这些数据代表了小鼠自发CB戒断的第一个证据，我们将系统地扩展这些研究，通过描绘必要的实验参数，以最大限度地利用无线电遥测，观察技术和操作性响应终点来测量自发和沉淀戒断的影响CB依赖的表达。我们的第一个目标是药理学，即，我们将研究用CB完全激动剂AM 2389长期治疗的小鼠，我们已经获得了令人鼓舞的初步数据。研究将继续在长期用非法药物9-四氢大麻酚（THC）或新计划的CB JWH-018和JWH-073治疗的小鼠中进行，预计每种激动剂的内在活性和作用持续时间将决定药物的毒性。 观察到的效果的大小。我们的第二个目标是确定的作用，上下文的影响，发展和表达的CB依赖。背景线索在维持药物寻求行为中的重要性在其他滥用物质中得到了很好的证实，但在CB文献中很少受到关注。我们建议具体配对特定的环境与注射利莫那班，并确定条件提示是否也可以“沉淀”CB撤退。我们的近期目标是确定CB依赖性发展的药理学和行为学机制。这些研究的直接影响将是增加对长期接触大麻和其他滥用CB的后果的理解。我们的长期目标是开发一个研究计划，其中这些模型将用于确定治疗大麻成瘾的潜在新疗法和管理策略。

DESCRIPTION (provided by applicant): Marijuana is the most commonly used illicit drug in the US, and the emergence of high efficacy synthetic cannabinoid (CB) drugs JWH-018 and JWH073 (sold as "Spice" and "K2") as popularly abused drugs indicate the gravity of the public health challenge posed by CB abuse-related disorders. Cannabis dependence is the third most prevalent substance abuse disorder, after nicotine and alcohol, and 30- 70% of chronic marijuana smokers experience symptoms of CB withdrawal. Despite this, relatively few studies have examined effects of chronically administered CBs in animals. To address this critical gap, we propose to develop robust animal models of CB dependence that can be used to better understand pharmacological and behavioral aspects of CB dependence. A hurdle to modeling CB dependence in animals has been the failure to observe an evident spontaneous withdrawal syndrome; symptoms often are mild and emerge over days. The CB antagonist, rimonabant, has been used to precipitate 'withdrawal', yet it remains unclear whether the effects of rimonabant reflect physical dependence or are the expression of other intrinsic effects of rimonabant. In preliminary studies in mice injected daily with a high efficacy CB1 agonist, AM2389, we found that rimonabant increased paw tremors and disrupted other behaviors; importantly, qualitatively similar results were obtained when the daily agonist injections were interrupted for 24-72 hrs. These data represent the first evidence of spontaneous CB withdrawal in mice and we will systematically extend these studies by delineating the experimental parameters necessary to maximize the expression of CB dependence using radiotelemetry, observation techniques, and operant responding endpoints to measure effects of both spontaneous and precipitated withdrawal. Our first aim is pharmacological, i.e., we will study mice treated chronically with the CB full agonist AM2389, with which we have obtained encouraging preliminary data. Studies will continue in mice treated chronically with the illicit drugs ¿9-tetrahydrocannabinol (THC), or the newly scheduled CBs JWH-018 and JWH-073, anticipating that the intrinsic activity and duration of action for each agonist will determine the magnitude of the observed effects. Our second aim is to identify the role of contextual influences on the development and expression of CB dependence. The importance of contextual cues in maintaining drug- seeking behavior is well-established for other abused substances but has received scant attention in the CB literature. We propose to specifically pair particular environments with injection of rimonabant, and determine if conditioned cues can also 'precipitate' CB withdrawal. Our immediate goals are to identify the pharmacological and behavioral mechanisms underlying the development of CB dependence. The direct impact of these studies will be an increased understanding of consequences of chronic exposure to marijuana and other abused CBs. Our long term goal is to develop a research program in which these models will be used to identify potential new therapies and management strategies for the treatment of cannabis addiction.