Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

描述（由申请人提供）：大麻的使用是一个公共健康问题。每天吸食大麻的人中，有一半以上出现戒断症状，这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风险是否随大麻素受体的药理功效而变化。此外，内源性大麻素激动剂（如anandamide）的药理学调节（如代谢或细胞摄取减少）是否产生治疗效果以及与直接大麻素激动剂相关的非首选效应较少尚不清楚。R01的竞争延续检查大麻素和非大麻素治疗大麻戒断的方法。本应用程序进一步研究行为效应、药理学（激动剂）功效和内源性大麻素水平的药理学操作之间的关系，预测人类大麻样效应。目的1使用利莫那班诱导的恒河猴大麻素戒断的药物鉴别试验来表征戒断后出现的神经药理学。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。将在恒河猴中对9-四氢大麻酚（9-THC）进行耐受性和交叉耐受性的研究。该目的还建立了一个具有高效大麻素激动剂的鉴别试验，并检查了对高效大麻素激动剂的依赖性，以鉴别刺激效应和明显的戒断迹象为指标。恒河猴的9-四氢大麻酚鉴别试验对外源性大麻胺高度敏感，该试验用于研究内源性大麻素的药理学操作以及内源性大麻素与9-四氢大麻酚之间的相互作用。目的3还研究了大麻素戒断的修改，阿南达胺及其代谢（URB 597）和摄取（AM 404）的抑制剂。这一竞争的延续解决了理解大麻素在预测大麻样中毒和依赖行为分析中的神经药理学的需要。总的来说，这一竞争继续的研究为开发大麻戒断和基于大麻素的新药物疗法提供了一个框架，这些疗法可能产生比大麻更少的副作用（即滥用和依赖责任）。公共卫生相关性：大麻的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）。这种竞争的延续解决了需要了解大麻素受体的机制，介导大麻的依赖责任和大麻素的潜在治疗效用。

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.