Cannabidiol: Lasting attenuation of ethanol seeking

 描述（由申请人提供）：该探索性/开发性项目旨在建立新的方法学作为PI实验室的研究工具，以探索有趣的初步发现的神经生物学基础，即用植物大麻素大麻二酚进行短暂治疗可显著减少乙醇（EtOH）寻求，其效果比治疗持续数月。导致酒精中毒的强迫性和慢性复发性的一个主要因素是由环境刺激引起的EtOH欲望，这些刺激已经成为药物主观效应的条件反射。事实上，尽管在非强化条件下频繁暴露，这些刺激引起乙醇寻求的功效在长期禁欲中持续存在，反映了酒精中毒的强迫性。在初步研究中，大麻二酚（CBD），大麻植物的主要非精神活性和非成瘾成分，在强迫性持续乙醇寻求的动物模型中显着减弱了恢复，在治疗终止后五个月仍然没有减弱。这些研究结果表明，CBD逆转神经可塑性与适应不良学习的基础EtOH渴望和复发，超越仅仅是短暂的药理学改善复发的脆弱性。因此，深入了解这些作用的机制可能对治疗药物的开发和理解强迫性乙醇寻求的神经和分子基础具有重要意义。该提案的目的是通过利用荧光激活细胞分选（FACS）和相关方法的最新进展来探索CBD持久的“抗恢复”作用的神经生物学基础。这些进展，由Co-I，Hope博士带头，允许快速高通量区域特异性识别（“神经映射”）编码特定行为的Fos表达神经元，同时以快速和定量的方式提供RNA，以允许表征来自单个大鼠的“行为激活”神经元的分子改变。该研究计划将扩展CBD对EtOH线索反应性的长期影响的探索，并在行为水平上确保EtOH寻求，并在实验室中建立FACS和相关方法，以确定与CBD寻求EtOH的持久衰减相关的大脑部位和基因表达。这些结果有望为CBD发挥作用的神经和分子靶点提供重要的见解，并为随后的全面项目奠定基础，这些项目包括系统研究已确定的神经靶点的因果作用和基因表达变化介导CBD干扰EtOH寻求，利用流式细胞仪鉴定关键基因及其表观遗传调控机制，负责CBD作用的持久性，从而揭示预防复发的新的治疗靶点。

 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 brief treatment with the phytocannabinoid cannabidiol significantly reduces ethanol (EtOH) seeking with effects that outlast treatment by several months. A major factor contributing to the compulsive and chronically relapsing nature of alcoholism is EtOH desire elicited by environmental stimuli that have become conditioned to the drug's subjective effects. Indeed, the efficacy of these stimuli to elicit EtOH seeking perseverates over long periods of abstinence despite frequent exposure under non-reinforced conditions, reflective of the compulsive nature of alcoholism. In preliminary studies, cannabidiol (CBD), the main non-psychoactive and non-addictive component of the cannabis sativa plant significantly attenuated reinstatement in an animal model of compulsive-like perseverating EtOH seeking, with effects that were still unabated five months after treatment termination. These findings suggest that CBD reverses neuroplasticity linked to maladaptive learning underlying EtOH 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 EtOH 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 EtOH cues and ensuing EtOH 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 EtOH 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 EtOH 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.