Treatment of Cannabinoid Withdrawal in Rhesus Monkeys

描述(申请人提供)：大麻的使用是一个公共卫生问题。超过一半的日常吸食大麻的人戒烟是吸食大麻的部分原因。然而，大麻中的大麻素产生了多种治疗效果(止痛和止吐效果)。虽然在建立大麻素行为效应的受体机制方面取得了进展，但尚不清楚大麻素在临床上的有用作用和滥用倾向是否会随着大麻素受体的药理作用而变化。此外，尚不清楚内源性大麻素激动剂(如阿南达胺)的药理调节(例如新陈代谢或细胞摄取减少)是否产生治疗效果，而与直接大麻素激动剂相关的非首选效应较少。这是R01的竞争性延续，研究了治疗大麻戒断的大麻素和非大麻素方法。这项应用进一步检查了行为效应、药理(激动剂)效力和在预测人类大麻样效应的分析中对内源性大麻素水平的药理操纵之间的关系。目的1采用利莫那班诱导恒河猴大麻素戒断的药物辨别试验，研究停药后戒断的神经药理学特征。目的2探讨大麻素受体激动剂的药理效应与行为效应之间的关系。在识别9-四氢大麻酚(9-THC)的恒河猴中，将检测不同疗效的大麻素之间的耐受性和交叉耐受性。这一目的还建立了一种使用高效大麻素激动剂的歧视试验，并检查了对高效大麻素激动剂的依赖，以歧视性刺激效应和明显的戒断迹象为指标。恒河猴对9-THC的辨别试验对外源性阿南达胺高度敏感，目的3用于研究内源性大麻素的药理作用以及内源性大麻素与9-THC之间的相互作用。目的3还研究了阿南达胺对大麻素戒断的修饰及其代谢抑制剂(URB 597)和摄取(AM 404)。这一竞争的延续解决了在预测大麻样中毒和依赖的行为分析中理解大麻类药物的神经药理学的需要。总体而言，这一竞争性延续中的研究为开发新的大麻戒断药物疗法和基于大麻的疗法提供了一个框架，这些疗法可能产生比大麻更少的不良影响(即滥用和依赖倾向)。与公共卫生相关：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了多种治疗效果(止痛和止吐效果)。这一竞争的延续解决了了解大麻素受体调节大麻依赖易感性和大麻类药物潜在治疗作用的机制的必要性。

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.