Cannabinoid Dependence Resubmission

大麻素依赖重新提交

• 批准号: 8637547
• 负责人: CAROL A PARONIS
• 金额: $ 23.7万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637547
• 关键词: Address; Agonist; Alcohols; Animal Model; Animals; Attention; Behavior; Behavioral; Behavioral Mechanisms; Biological Assay; Cannabinoids; Cannabis; Chronic; Cues; Data; Dependence; Development; Disease; Drug Exposure; Environment; Environmental Risk Factor; Event; Exposure to; Failure; Force of Gravity; Foundations; Funding; Future; Goals; Human; Illicit Drugs; In Vitro; Individual; Injection of therapeutic agent; Investigation; Laboratories; Laboratory Animals; Laboratory Study; Literature; Marijuana; Marijuana Dependence; Measures; Mediating; Modeling; Mus; Nature; Nicotine; Outcome; Patients; Pharmaceutical Preparations; Physical Dependence; Physiological; Property; Public Health; Relapse; Research; Role; Schedule; Severities; Smoker; Spices; Stimulus; Substance Withdrawal Syndrome; Substance abuse problem; Symptoms; Techniques; Tetrahydrocannabinol; Therapeutic; Time; Tremor; United States; Withdrawal; addiction; combat; conditioning; drug craving; drug efficacy; drug of abuse; drug seeking behavior; experience; improved; novel; novel therapeutics; pre-clinical; programs; public health relevance; research study; response; rimonabant; tool; treatment strategy

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.

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JWH073（以“Spice”和“K2”出售）作为普遍滥用的药物的出现表明了大麻滥用相关疾病带来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药物滥用障碍，30- 70%的慢性大麻吸烟者有大麻戒断症状。尽管如此，相对较少的研究检查了长期服用CBs对动物的影响。为了解决这一关键的差距，我们建议开发强大的CB依赖动物模型，可以用来更好地理解CB依赖的药理学和行为学方面。在动物中建立CB依赖模型的一个障碍是未能观察到明显的自发戒断综合征；症状通常很轻微，持续数天。CB拮抗剂利莫那班已被用于沉淀“戒断”，但目前尚不清楚利莫那班的作用是反映身体依赖还是利莫那班的其他内在作用的表达。在对每天注射高效CB1激动剂AM2389的小鼠进行的初步研究中，我们发现利莫那班增加了脚掌震颤并扰乱了其他行为；重要的是，当每日激动剂注射中断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戒断的第一个证据，我们将系统地扩展这些研究，通过使用无线电遥测、观察技术和操作响应终点来描述最大限度地表达CB依赖性所需的实验参数，以测量自发戒断和沉淀戒断的影响。我们的第一个目标是药理学，即我们将研究长期使用CB完全激动剂AM2389治疗的小鼠，我们已经获得了令人鼓舞的初步数据。研究将继续在长期使用非法药物- 9-四氢大麻酚（THC）或新计划的CBs 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其治疗效果