Implementation of novel methodology to study the anti-relapse potential of cannabidiol

实施新方法来研究大麻二酚的抗复发潜力

• 批准号: 9318822
• 负责人: Friedbert Weiss
• 金额: $ 17.33万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318822
• 关键词: Abstinence; Address; Aftercare; Animal Model; Area; Attenuated; Behavior; Behavior Control; Behavioral; Brain; Brain region; Cannabidiol; Cannabis sativa plant; Cocaine; Cocaine Dependence; Cues; Data; Development; Disease; Dose; Epigenetic Process; Fluorescence-Activated Cell Sorting; Foundations; Future; Gene Expression; Genes; Health; Housing; Investigation; Knowledge; Laboratories; Link; Maps; Mediating; Methodology; Modeling; Molecular; Molecular Target; Nature; Neurobiology; Neuronal Plasticity; Neurons; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Procedures; RNA; Rattus; Relapse; Research; Research Project Grants; Role; Site; Stimulus; Testing; Time; animal efficacy; attenuation; base; brain tissue; brief intervention; cocaine exposure; cocaine relapse prevention; craving; design; disorder later incidence prevention; drug development; insight; method development; new therapeutic target; novel; phytocannabinoid; relating to nervous system; response; tool; treatment effect

 DESCRIPTION (provided by applicant): This exploratory/developmental project is designed is to establish novel methodology as a research tool in the PI's laboratory to explore the neurobiological basis of intriguing preliminary findings that the phytocannabinoid cannabidiol (CBD) attenuates cocaine seeking with effects that significantly outlast treatment. A major factor contributing to the compulsive and chronically relapsing nature of cocaine addiction is drug desire elicited by environmental stimuli that have become conditioned to cocaine's subjective effects. In animals, the efficacy of these stimuli to elicit cocaine seeking perseverates over long periods of abstinence despite frequent exposure under non-reinforced conditions, reflective of the compulsive nature of cocaine addiction. In preliminary studies, CBD (the main non-psychoactive and non-addictive component of the cannabis sativa plant) significantly attenuated reinstatement in an animal model of perseverating, compulsive- like cocaine seeking, with effects that were still unabated six weeks after treatment termination. These findings suggest that CBD reverses neuroplasticity underlying cocaine craving and relapse beyond mere transient pharmacological amelioration of vulnerability to relapse. Insight into the mechanisms underlying these effects may therefore have major implications for treatment drug development and understanding of the neural and molecular basis of compulsive cocaine seeking. The objective of this proposal is to explore the neurobiological basis of CBD's lasting "anti-reinstatement" actions by exploiting recent advances in fluorescence-activated cell sorting (FACS) and associated methodologies. These advances, spearheaded by the Co-I, Dr. Hope, permit rapid high-throughput regionally specific identification ("neural mapping") of Fos-expressing neurons that encode specific behaviors while at the same time providing RNA in a rapid and quantitative manner to permit characterization of molecular alterations in "behaviorally activated" neurons from single rats. The research plan is to extend the exploration of CBD's long-lasting effects on responsiveness to cocaine cues and ensuing cocaine seeking at the behavioral level, and to establish FACS and associated methodologies in the lab to identify brain sites and gene expression linked to the lasting attenuation of cocaine seeking by CBD. The results are expected to provide essential insight into neural and molecular targets through which CBD exerts its actions and to lay the foundations for subsequent full-scale projects ranging from systematic investigation of causal roles of identified neural targets and gene expression changes in mediating CBD's interference with cocaine seeking, to utilization of FACS for the identification of key genes and their epigenetic regulatory mechanisms responsible for the persistence of CBD's actions, and thereby to reveal novel therapeutic targets for relapse prevention.

 描述（由应用程序提供）：该探索性/发展项目旨在建立新方法作为PI实验室中的研究工具，以探索有趣的初步发现的神经生物学基础，即植物大麻素大麻二醇（CBD）减弱可卡因可与可卡因寻求相关的效果，这些效果显着估计了治疗的影响。可卡因成瘾的强迫性和长期复发性质的一个主要因素是由环境刺激引起的药物，这些药物已得到可卡因的主观影响。在动物中，这些刺激的有效性引起可卡因寻求持久的长期 节制时期尽管经常在非增强条件下暴露，反映了可卡因成瘾的强迫性质。在初步研究中，CBD（大麻sativa植物的主要非精神活性和非成分成分）在持续的，强迫性的可卡因寻求动物模型中显着减弱了恢复原状，其效果在治疗终止后六周仍未减弱。这些发现表明，CBD逆转了可卡因渴望和继电器的神经可塑性，超出了短暂的药物对缓解脆弱性的改善。因此，深入了解这些作用潜在的机制可能对治疗药物的开发以及对强迫性可卡因寻求的神经系统和分子基础的理解具有重大影响。该提案的目的是通过利用荧光激活的细胞分选（FACS）和相关方法的最新进展来探索CBD持久的“抗重新陈述”作用的神经生物学基础。这些进步以Co-I为首的Hope博士，允许对表达特定行为的表达FOS的神经元快速高通量区域特定的鉴定（“神经映射”），同时以快速和定量的方式提供RNA，以允许在“行为激活”的神经元中的分子变化中提供RNA。该研究计划是扩展对CBD对可卡因提示反应的长期影响，并确保在行为层面寻求可卡因的响应能力，并在实验室中建立FACS和相关方法，以识别与CBD对可卡因寻求的持久衰减有关的大脑位点和基因表达。 The results are expected to provide essential insight into neural and molecular targets through which CBD exerts its actions and to lay the foundations for subsequent sequence full-scale projects ranging from systematic investigation of causal roles of identified neural targets and gene expression changes in mediating CBD's interference with cocaine seeking, to utilization of FACS for the identification of key genes and their epigenetic regulatory mechanisms responsible for CBD行动的持久性，从而揭示了预防救济的新型治疗靶标。