Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

摘要 海洋生物的使用是一个公共卫生问题。每天超过一半的时间内发生的戒断 大麻使用者对吸食大麻负有部分责任。然而， 大麻产生多种治疗效果（止痛和止吐效果）。而 在建立行为神经元的受体机制方面已经取得了进展， 大麻素的作用，目前尚不清楚是否临床有用的行动和滥用的责任， 大麻素作为对大麻素受体的药理功效的函数而变化。而且 尚不清楚是否有药理学调节（例如代谢或细胞摄取减少） 内源性大麻素激动剂（例如大麻素酰胺）产生治疗效果， 与直接大麻素激动作用相关的非优选作用。这种竞争的延续 R 01研究了用于治疗大麻戒断的大麻素和非大麻素方法。 本申请进一步研究了行为效应、药理学效应和免疫学效应之间的关系。 （激动剂）功效和预测测定中内源性大麻素水平的药理学操作 大麻对人体的影响目的1使用利莫那班诱导的药物鉴别试验 恒河猴大麻素戒断以表征戒断的神经药理学 在停止治疗后出现。目标2探讨了 对大麻素受体的药理学（激动剂）功效和行为效应。容忍和 将在恒河猴中检测不同功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个歧视分析， 并检查对高效大麻素的依赖性 激动剂，由区别性刺激效应和明显的戒断症状指示。9-THC 恒河猴的鉴别试验对外源性给药高度敏感 大麻素，并且该测定在目的3中用于检查大麻素的药理学操作。 内源性大麻素和内源性大麻素与9-THC之间的相互作用。Aim 3 检查大麻素戒断的大麻素及其代谢抑制剂的修改 (URB 597）和摄取（AM 404）。这种竞争性的延续解决了以下需求： 了解大麻素在行为测定中的神经药理学， 大麻般的中毒和依赖总的来说，在这个竞争性的延续中， 为开发大麻戒断的新药物疗法提供了一个框架， 基于大麻素的治疗剂可能产生较少的不良反应（即滥用和 依赖性（dependence liability）比大麻。

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.