Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

描述（由申请人提供）：海洋生物使用是一个公共卫生问题。超过一半的日常大麻使用者的戒断症状在一定程度上是吸食大麻的原因。然而，大麻中的大麻素产生多种治疗作用（镇痛和止吐作用）。虽然在建立大麻素行为效应的受体机制方面取得了进展，但尚不清楚大麻素的临床有用作用和滥用倾向是否随大麻素受体的药理学功效而变化。此外，尚不清楚内源性大麻素激动剂（例如大麻素酰胺）的药理学调节（例如代谢或细胞摄取减少）是否产生治疗效果和较少的与直接大麻素激动相关的非优选效果。R 01的这种竞争性延续研究了大麻素和非大麻素治疗大麻戒断的方法。本申请进一步检查了行为效应、药理学（激动剂）功效和在预测人类大麻样效应的测定中内源性大麻素水平的药理学操纵之间的关系。目的1使用利莫那班诱导的恒河猴大麻素戒断的药物辨别试验来表征停药后出现的戒断的神经药理学。目的2探讨大麻素受体的药理学（激动剂）功效与行为效应之间的关系。将在辨别9-四氢大麻酚（9-THC）的恒河猴中检查功效不同的大麻素之间的耐受性和交叉耐受性。该目标还建立了高效大麻素激动剂的区分测定，并检查对高效大麻素激动剂的依赖性，通过区分刺激效应和明显的戒断迹象来指示。恒河猴中的9-THC辨别试验对外源性施用的大麻素高度敏感，并且该试验用于目的3以检查内源性大麻素的药理学操作以及内源性大麻素与9-THC之间的相互作用。目的3还检查大麻素戒断的大麻素及其代谢（URB 597）和摄取（AM 404）的抑制剂的修改。这种竞争性的延续解决了在预测大麻样中毒和依赖的行为测定中理解大麻素的神经药理学的需要。总的来说，在这种竞争性的继续研究提供了一个框架，开发新的药物治疗大麻戒断和大麻素为基础的治疗，可以产生更少的不良影响（即滥用和依赖的责任）比大麻。公共卫生相关性：海洋生物使用仍然是一个公共卫生问题。然而，大麻中的大麻素产生多种治疗作用（镇痛和止吐作用）。这种竞争性的延续解决了理解大麻素受体介导大麻依赖性和大麻素潜在治疗效用的机制的需要。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Marijuana use continues to be a public health concern. However, cannabinoids in marijuana produce a variety of therapeutic effects (analgesic and anti-emetic effects). This competing continuation addresses a need to understand mechanisms at cannabinoid receptors that mediate the dependence liability of marijuana and the potential therapeutic utility of the cannabinoids.