Reducing the deleterious effects of synthetic cannabinoid withdrawal on emotionality and motivation

合成大麻素受体激动剂的使用，最初是作为研究工具和 后来喷洒在植物材料上，作为大麻的合法替代品出售，近年来有所增加 数年来，尽管有人试图限制它们的商业供应。这至少部分是由于 人们普遍认为大麻素是一种“软毒品”，戒断症状相对较轻。 然而，越来越多的文献表明，大麻使用障碍影响到许多使用者，主要是 症状是情绪性的(如焦虑、抑郁、激动)、躯体的(如胃部不适、睡眠 以及认知(例如，对大麻的渴望)。不足为奇的是，缓解了 禁欲带来的症状是复发的常见原因。因此，有必要 开发治疗大麻素依赖的新疗法。 目前关于大麻依赖的临床前研究使用躯体结果来量化 大麻戒断。这些模型是有用的，但并没有探讨 大麻类药物的戒断在人类中最为突出，并直接导致复发。我们的 初步数据表明，从植物大麻素Δ9-四氢大麻酚(THC)， 或合成大麻素JWH-018，显著减少大理石埋藏，这是 激荡，并在尾部悬挂试验中增加挣扎。目标1的目标是充分 描述合成大麻素戒断对临床前测量的行为影响 情绪性和积极性。我们将用典型的合成大麻素反复治疗小鼠 激动剂JWH-018或CP55,940，并诱导催促和自发戒断，以量化 在一系列测试中的戒断行为，以模拟情绪、动机和躯体迹象 戒烟。 除了行为干预外，辅助治疗也得到了很大程度的应用 成功地减少了药物依赖。拟议研究的目标2的目标是正常化 JWH-018对CB1的正变构调节引起的戒断行为改变 受体。我们建议给小鼠服用正负变构调节剂。 正在经历戒断，并测试我们未发表的初步行为分析的变化 数据表明，大麻类药物的戒断会改变这一点。预计正变构调节 将减轻JWH-018戒断诱导的行为改变。成功地完成了 拟议的项目将为更大规模的神经行为项目提供初步数据，目标是 为人类大麻素依赖研究提供信息。

The use of synthetic cannabinoid receptor agonists, first developed as research tools and later sprayed on plant material and sold as a legal alternative to cannabis, has increased in recent years, despite attempts to limit their commercial availability. This is due at least in part to the common perception of cannabinoids as a "soft drugs" with relatively mild withdrawal symptoms. However, a growing literature indicates Cannabis Use Disorder affects many users, the primary symptoms being emotional (e.g., anxiety, depression, agitation), somatic (e.g., gastric upset, sleep disturbance), and cognitive (e.g., cravings for cannabis). Not surprisingly, alleviating the aversive symptoms brought about by abstinence is common cause of relapse. Thus, there is a need to develop new treatments for cannabinoid dependence. Current preclinical research on cannabis dependence uses somatic outcomes to quantify cannabis withdrawal. These models have been useful but do not explore the emotional aspects of cannabinoids withdrawal that are most salient in humans and contribute directly to relapse. Our preliminary data indicate that withdrawal from the phytocannabinoid Δ9-tetrahydrocannabinol (THC), or the synthetic cannabinoid JWH-018, significantly decreases marble burying, a proxy measure of agitation, and increases struggling in the tail suspension test. The goal of Aim 1 is to fully characterize the behavioral effects of synthetic cannabinoid withdrawal on preclinical measures of emotionality and motivation. We will treat mice repeatedly with the prototypical synthetic cannabinoid agonist JWH-018 or CP55,940 and induce precipitated and spontaneous withdrawal, to quantify withdrawal behaviors in a battery of tests to model emotion, motivation, and somatic signs of withdrawal. In addition to behavioral interventions, adjuvant therapies have been used with much success to reduce drug dependence. The goal of Aim 2 of the proposed studies is to normalize JWH-018 withdrawal-induced behavioral changes by positive allosteric modulation of the CB1 receptor. We propose to administer a positive and a negative allosteric modulator to mice undergoing withdrawal, and to test alterations in behavioral assays that our unpublished preliminary data indicate are altered by cannabinoid withdrawal. It is expected that positive allosteric modulation will attenuate JWH-018 withdrawal-induced behavioral changes. The successful completion of the proposed project will yield preliminary data for larger scale neurobehavioral project, with the goal of informing human cannabinoid dependence research.