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

项目摘要 药物滥用仍然是一个重大的且不断升级的公共卫生问题，因为药物滥用的比率和 在过去的十年里，过量死亡一直在不断加速。而阿片类药物主要是推动 过量死亡的灾难性扩大，与使用兴奋剂相关的死亡率的回升 毒品，以及阿片类药物和兴奋剂药物的共同滥用，在最近几年很明显。虽然治疗方案是针对 存在阿片类药物使用障碍的管理，他们受到患者依从性差的困扰，或者是他们自己 阿片类激动剂，因此具有依赖、滥用和死亡的高风险。对于兴奋剂使用障碍， 目前还没有批准的治疗方案。目前阿片类药物现有治疗方法的缺点 使用障碍，以及完全缺乏任何兴奋剂使用障碍的治疗选择，清楚地表明有必要 减少阿片类药物和兴奋剂药物滥用相关影响的新选择。大麻素2型(CB2) 受体激动剂是一个潜在的靶点，已经显示出在对抗与滥用相关的 阿片类药物和兴奋剂的影响。然而，人类很少单独使用药物，这表明 单一药物滥用的药物使用障碍候选治疗的临床前研究 准确地反映人类使用药物的方式，可能不能真实地反映其治疗潜力 世界场景。因此，本申请中提出的研究旨在检查CB2受体的作用 激动剂对阿片类药物、兴奋剂和阿片/兴奋剂混合物的滥用相关影响。这些研究将 检查CB2受体激动剂对物质中最有问题的两个方面的治疗潜力 使用障碍：吸毒行为和复发。AIM 1中的研究将检验CB2受体的作用 芬太尼、甲基苯丙胺和芬太尼/甲基苯丙胺混合液的自身给药激动剂 一种食物与药物的选择程序。AIM 2的研究将检验CB2受体激动剂对 恢复以前因芬太尼、甲基苯丙胺和 芬太尼/甲基苯丙胺混合物。这些研究将为未来对 CB2受体激动剂对阿片类药物、兴奋剂和多物质的其他问题效应的治疗作用 使用障碍对身体依赖和戒断、身体吸毒行为的影响 依赖受试者，以及阿片类药物的呼吸性抑制作用。此外，博士后培养计划 在本申请中提出的建议包括获得重要的新科学技能以及其他 旨在促进申请者从博士后实习生过渡到独立博士后的有组织的活动 调查员。

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.