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

减少合成大麻素戒断对情绪和动机的有害影响

基本信息

批准号：
10134039
负责人：
Steven G. Kinsey
金额：
$ 6.58万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10134039
关键词：
Reducing deleterious effects synthetic cannabinoid

项目摘要

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.

合成大麻素受体激动剂的使用首先是作为研究工具开发的，后来喷洒在植物材料上，作为大麻的法律的替代品出售，多年来，尽管试图限制其商业可用性。这至少部分是由于大麻素是一种“软性毒品”，戒断症状相对较轻。然而，越来越多的文献表明，大麻使用障碍影响许多用户，主要是情绪化症状（例如，焦虑、抑郁、激动），躯体（例如，胃部不适，睡眠干扰），和认知（例如，对大麻的渴望）。毫不奇怪，减轻厌恶戒断带来的症状是复吸的常见原因。因此，有必要开发大麻素依赖的新疗法。目前对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，但没有探讨情感方面的问题。大麻素戒断在人类中最突出，并直接导致复发。我们初步数据表明，从植物大麻素Δ9-四氢大麻酚（THC）中戒断，或合成大麻素JWH-018，显着减少大理石埋葬，一个代理措施，搅拌，并在尾部悬挂试验中增加挣扎。目标1的目标是充分表征合成大麻素戒断对临床前测量的行为影响，情绪和动机。我们将用典型的合成大麻素反复治疗老鼠激动剂JWH-018或CP 55，940，并诱导沉淀和自发戒断，以定量在一系列测试中的退缩行为，以模拟情绪，动机和戒断除了行为干预外，辅助治疗也被用于许多成功减少药物依赖。拟议研究的目标2是标准化 JWH-018通过CB 1的正向别构调节引起戒断行为变化受体的我们建议给小鼠施用正变构调节剂和负变构调节剂经历戒断，并测试行为测定的变化，我们未发表的初步数据显示，大麻素戒断会改变。预期正变构调节会减弱JWH-018戒断引起的行为变化圆满完成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。