Cannabinoid type 2 receptors as a therapeutic target for substance use disorders

大麻素 2 型受体作为物质使用障碍的治疗靶点

• 批准号: 10606224
• 负责人: Lawrence Michael Carey IV
• 金额: $ 0.84万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2023-02-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606224
• 关键词: Acceleration; Address; Agonist; Behavior; CNR1 gene; CNR2 gene; COVID-19 pandemic; Cessation of life; Clinical; Clinical Trials; Cocaine; Communication; Cues; Dependence; Development; Disease; Drug abuse; Drug usage; Epidemic; Evaluation; Fentanyl; Food; Foundations; Grant; Health; Health Personnel; Human; Impaired cognition; Individual; Infusion procedures; Injections; Laboratories; Macaca mulatta; Medication Management; Methamphetamine; Modeling; Monkeys; Mus; National Institute of Drug Abuse; Nicotine; Opiate Addiction; Opioid; Opioid Analgesics; Opioid agonist; Opioid replacement therapy; Overdose; Pain; Pathologic; Pharmaceutical Preparations; Physical Dependence; Policies; Population; Postdoctoral Fellow; Procedures; Public Health; Relapse; Research; Research Personnel; Research Training; Rewards; Risk; Rodent; Safety; Self Administration; Solid; Stimulant; Structure; Substance Use Disorder; Sucrose; Testing; Therapeutic; Toxic effect; Training; Translations; Treatment Efficacy; Twin Multiple Birth; Ventilatory Depression; Withdrawal; abuse liability; antagonist; cannabinoid receptor; career; career development; cocaine self-administration; combat; compliance behavior; conditioned place preference; design; drug of abuse; effective therapy; fentanyl self-administration; high risk; interest; model organism; mortality; nonhuman primate; novel; opioid abuse; opioid overdose; opioid use; opioid use disorder; overdose death; polysubstance abuse; polysubstance use; post-doctoral training; preclinical study; preference; prescription opioid; response; responsible research conduct; side effect; skills; stimulant abuse; stimulant use; stimulant use disorder; substance use treatment; synthetic opioid; therapeutic target; treatment strategy; vigilance

Project Summary Drug abuse remains a significant, and escalating, public health problem as rates of drug abuse and overdose deaths have been accelerating incessantly over the last decade. While opioids have primarily driven this catastrophic expansion in overdose deaths, a resurgence in mortality associated with the use of stimulant drugs, and the co-abuse of opioids and stimulant drugs, is evident in recent years. While treatment options for the management of opioid use disorder exist, they are plagued by poor patient compliance or are themselves opioid agonists and therefore possess a high risk for dependence, abuse, and death. For stimulant use disorder, there are currently no approved treatment options. The shortcomings of currently available treatments for opioid use disorder, and the total lack of any treatment options for stimulant use disorder, clearly indicate the need for novel options to reduce the abuse-related effects of opioid and stimulant drugs. Cannabinoid type 2 (CB2) receptor agonists are one potential target that have demonstrated some promise in combating the abuse-related effects of both opioids and stimulant drugs. However, humans rarely use drugs in isolation indicating the preclinical study of candidate treatments for substance use disorders on single drugs of abuse does not accurately reflect the way drugs are used by humans and may not represent their therapeutic potential in real world scenarios. Therefore, the research proposed in this application aims to examine the effects of CB2 receptor agonists on the abuse-related effects of opioids, stimulants, and opioid/stimulant mixtures. These studies will examine the therapeutic potential of CB2 receptor agonists on 2 of the most problematic aspects of substance use disorders: drug taking behavior, and relapse. Studies in Aim 1 will examine the effects of CB2 receptor agonists on the self-administration of fentanyl, methamphetamine, and fentanyl/methamphetamine mixtures in a food versus drug choice procedure. Studies in Aim 2 will examine the effects of CB2 receptor agonists on the reinstatement of responding previously reinforced by fentanyl, methamphetamine, and fentanyl/methamphetamine mixtures. These studies will provide the foundation for future research into the therapeutic utility of CB2 receptor agonists on other problematic effects of opioid, stimulant, and polysubstance use disorders including their effects on physical dependence and withdrawal, drug taking behavior in physically dependent subjects, and the ventilatory depressant effects of opioids. Moreover, the postdoctoral training plan proposed in this application encompasses the acquisition of vital new scientific skills in addition to other structured activities designed to facilitate the applicants transition from postdoctoral trainee to independent investigator.

项目摘要 药物滥用仍然是一个严重的、不断升级的公共卫生问题， 在过去十年中，过量死亡不断加速。虽然阿片类药物主要驱动 过量死亡的灾难性扩大，与使用兴奋剂有关的死亡率的回升， 近年来，滥用阿片类药物以及同时滥用阿片类药物和兴奋剂药物的现象十分明显。虽然治疗选择 存在阿片样物质使用障碍管理，它们受到患者依从性差的困扰，或者它们本身 阿片激动剂，因此具有依赖性、滥用和死亡的高风险。对于兴奋剂使用障碍， 目前没有批准的治疗方案。目前阿片类药物治疗的缺点 使用障碍，以及对兴奋剂使用障碍完全缺乏任何治疗选择，清楚地表明需要 减少类阿片和兴奋剂药物滥用相关影响的新选择。大麻素2型（CB 2） 受体激动剂是一种潜在的靶点，在对抗滥用相关的 阿片类药物和兴奋剂的作用。然而，人类很少单独使用药物， 对单一药物滥用的物质使用障碍的候选治疗的临床前研究不 准确反映人类使用药物的方式，可能无法代表其真实的治疗潜力 世界情景因此，本申请中提出的研究旨在检查CB 2受体的作用 激动剂对阿片类药物、兴奋剂和阿片类药物/兴奋剂混合物的滥用相关作用的影响。这些研究将 检查CB 2受体激动剂在物质的两个最有问题的方面的治疗潜力 使用障碍：吸毒行为和复吸。目的1中的研究将检查CB 2受体的作用 芬太尼、甲基苯丙胺和芬太尼/甲基苯丙胺混合物的自我给药的激动剂 食物和药物的选择程序目的2中的研究将检查CB 2受体激动剂对 恢复以前由芬太尼，甲基苯丙胺和 芬太尼/甲基苯丙胺混合物。这些研究将为今后的研究提供基础， CB 2受体激动剂对阿片样物质、兴奋剂和多物质的其它问题作用的治疗效用 使用障碍，包括其对身体依赖和戒断的影响，身体上的吸毒行为， 依赖性受试者，以及阿片类药物的治疗作用。此外，博士后培养计划 在这个应用程序中提出的包括收购重要的新的科学技能，除了其他 结构化的活动，旨在促进申请人从博士后实习生到独立的过渡 调查员