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，首先作为研究工具开发后来喷洒在植物材料上，并作为大麻的合法替代品出售，最近有所增加多年来，目的地试图限制其商业可用性。这至少部分是由于对大麻素作为一种“软药物”的常见感知，具有相对轻微的戒断症状。但是，越来越多的文献表明大麻使用障碍会影响许多用户，主要是症状是情感上的（例如焦虑，抑郁，躁动），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，减轻了厌恶性禁欲带来的症状是退休的常见原因。那是有必要的开发新的大麻素依赖性治疗方法。当前对大麻依赖的临床前研究使用躯体结果来量化大麻退出。这些模型很有用，但没有探索大麻素的戒断是人类最突出的，直接导致退休。我们的初步数据表明从植物大麻素Δ9-四氢大麻酚（THC），或合成的大麻素JWH-018，显着降低了大理石掩埋搅动，并在尾悬架测试中增加了苦难。目标1的目标是完全表征合成大麻素戒断对临床前测量的行为影响情绪和动力。我们将用原型合成大麻素反复治疗小鼠激动剂JWH-018或CP55,940，并衍生出沉淀和赞助戒断，以量化在一系列测试中提取行为，以建模情绪，动机和躯体迹象提取。除了行为干预外，调整疗法已被多大使用成功减少药物依赖性。拟议研究的目标2的目标是正常化 JWH-018撤回引起的行为变化通过CB1的正变构调制受体。我们建议对小鼠施用阳性和负变构调节剂进行退出，并测试我们未发表的初步的行为测定法的更改大麻素戒断会改变表明的数据。预计阳性变构调节将减弱JWH-018撤回引起的行为变化。成功完成拟议的项目将为大规模神经行为项目产生初步数据，目的是告知人类大麻素依赖研究。