Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

摘要 大麻的使用是一个公共卫生问题。一天中有一半以上的人戒烟 吸食大麻的人对吸食大麻负有部分责任。然而，大麻类物质在 大麻有多种治疗效果(止痛和止吐)。而当 在建立行为基础上的受体机制方面已经取得了进展 对于大麻素的影响，尚不清楚其临床有用的行为和滥用的责任 大麻素随着大麻素受体的药理作用而变化。此外，它还 尚不清楚药物调节(例如，新陈代谢或细胞摄取减少)是否 内源性大麻素激动剂(如阿南达胺)产生治疗效果，而 与直接大麻素激动剂相关的非首选效应。这种相互竞争的延续 R01研究了大麻素和非大麻素治疗大麻戒断的方法。 这个应用程序进一步检查了行为效应、药理作用 (激动剂)疗效和药物操纵内源性大麻素水平的预测分析 对人类产生类似大麻的影响。目的1使用利莫那班诱导的药物鉴别分析 恒河猴大麻素戒断的神经药理学特征 一旦停止治疗就会出现这种情况。目标2探讨了 大麻素受体的药理(激动剂)疗效和行为效应。容忍度和 将在恒河猴身上检测不同药效的大麻素之间的交叉耐受性 鉴别9-四氢大麻酚(9-THC)这一目标还建立了一种辨别试验 使用高效大麻素激动剂，并检查对高效大麻素的依赖 激动剂，以歧视性刺激效应和明显的戒断迹象为指标。The？9-THC 恒河猴辨别试验对外源性给药高度敏感 ANANDAME，并在目标3中使用该方法来检查药物操纵 内源性大麻素及其与9-THC的相互作用。AIM 3也 研究阿南达胺及其代谢抑制剂对大麻素戒断的影响 (URB 597)和摄取(AM 404)。这种相互竞争的延续解决了对 在行为分析中了解大麻素的神经药理学预测 像大麻一样的醉意和依赖。总而言之，在这一竞争延续中的研究 为开发大麻戒断的新药物疗法提供框架，并 以大麻素为基础的疗法，可产生较少的不良反应(即滥用和 依赖责任)，而不是大麻。

Abstract Marijuana use is a public health concern. Withdrawal that occurs in over one-half of daily marijuana users is responsible, in part, for marijuana smoking. However, cannabinoids in marijuana produce a variety of therapeutic effects (analgesic and anti-emetic effects). While progress has been made toward establishing receptor mechanisms underlying the behavioral effects of cannabinoids, it is not clear whether the clinically useful actions and abuse liability of cannabinoids vary as a function of pharmacologic efficacy at cannabinoid receptors. Moreover, it is not clear whether pharmacologic modulation (e.g. decreased metabolism or cellular uptake) of endogenous cannabinoid agonists (e.g. anandamide) produces therapeutic effects and less of the non-preferred effects associated with direct cannabinoid agonism. This competing continuation of an R01 examines cannabinoid and non-cannabinoid approaches for treating marijuana withdrawal. This application further examines relationships between behavioral effects, pharmacologic (agonist) efficacy, and pharmacologic manipulation of endocannabinoid levels in assays predictive of marijuana-like effects in humans. Aim 1 uses a drug discrimination assay of rimonabant-induced cannabinoid withdrawal in rhesus monkeys to characterize the neuropharmacology of withdrawal that emerges upon discontinuation of treatment. Aim 2 explores relationships between pharmacologic (agonist) efficacy at cannabinoid receptors and behavioral effects. Tolerance and cross-tolerance among cannabinoids that vary in efficacy will be examined in rhesus monkeys discriminating ¿9-tetrahydrocannabinol (¿9-THC). This aim also establishes a discrimination assay with a high efficacy cannabinoid agonist and examines dependence to a high efficacy cannabinoid agonist, indexed by discriminative stimulus effects and overt signs of withdrawal. The ¿9-THC discrimination assay in rhesus monkeys was highly sensitive to exogenously administered anandamide, and this assay is used in Aim 3 to examine pharmacologic manipulation of endogenous cannabinoids and interactions between endocannabinoids and ¿9-THC. Aim 3 also examines modification of cannabinoid withdrawal by anandamide and inhibitors of its metabolism (URB 597) and uptake (AM 404). This competing continuation addresses a need for understanding the neuropharmacology of cannabinoids in behavioral assays predictive of marijuana-like intoxication and dependence. Collectively, studies in this competing continuation provide a framework for developing novel pharmacotherapies of marijuana withdrawal and cannabinoid-based therapeutics that could produce fewer adverse effects (i.e. abuse and dependence liability) than marijuana.