Pharmacotherapy of Cannabinoid Withdrawal: Pre-Clinical Studies

该R01是根据RFA-DA-09-001（大麻相关疾病药物开发）提交的，已被修改以适应2年的预算。该拨款建议在非人类灵长类动物中使用大麻素戒断的临床前测量方法来确定大麻依赖的潜在药物治疗方法。超过一半的日常大麻使用者在停止使用后会出现戒断症状，据报道，这促使了大麻的吸食。在临床实验室中，大麻戒断的药物治疗与减少大麻复发有关，因此，是促进戒断的可行策略。该应用程序解决了临床前分析的迫切需要，可以提供快速有效的药物测试，以减轻大麻素戒断的能力。大麻素拮抗剂利莫那班将为接受Δ9-tetrahydrocannabinol慢性治疗的恒河猴提供戒断指数，Δ9-tetrahydrocannabinol是大麻素的主要滥用和依赖责任。歧视性刺激效应将提供一种衡量个人退出体验的方法。将检查药物是否能够改变鉴别刺激效应，以及其他戒断症状，包括摇头和夜间在家笼子里活动增加（即睡眠中断）。目的1将检查Δ9-tetrahydrocannabionol单独和α2-肾上腺素能激动剂（可乐定和洛非昔定）联合对大麻素戒断的影响。据报道，这种组合比单独使用任何一种药物更有效地减轻了大麻的戒断反应。定量药理学（即等密度）分析将用于检查药物组合对大麻素戒断的衰减是添加剂，小于添加剂，还是大于添加剂（协同）。协同药物组合可能是特别有效的治疗方法。目的2评估睡眠中断的药物治疗作为一种减轻大麻素戒断的策略，这种戒断是由白天的鉴别刺激效应和头抖引起的。用于减轻睡眠中断和第二天大麻素戒断症状的药物将包括苯二氮卓类药物（唑吡坦或安比恩）、5HT2A拮抗剂M100907和褪黑激素激动剂拉美替恩（Rozerem）。总的来说，这些具体目标为开发大麻戒断的新型药物疗法提供了一个框架，可以显着减少大麻的使用和依赖。

This R01, submitted in response to RFA-DA-09-001 (Medications Development for Cannabis-Related Disorders), has been modified to accommodate a 2-year budget. The grant proposes using pre-clinical measures of cannabinoid withdrawal in non-human primates to identify potential pharmacotherapies of marijuana dependence. Over one-half of daily marijuana users experience withdrawal upon discontinuation of use, which is reported to drive marijuana smoking. Pharmacotherapy of marijuana withdrawal is associated with decreased relapse to marijuana use in the clinical laboratory and, therefore, is a viable strategy for promoting abstinence. This application addresses a compelling need for pre-clinical assays that can provide rapid and efficient testing of drugs for their capacity to attenuate cannabinoid withdrawal. The cannabinoid antagonist rimonabant will provide an index of withdrawal in rhesus monkeys receiving chronic treatment with Δ9-tetrahydrocannabinol, the cannabinoid primarily responsible for the abuse and dependence liability of marijuana. Discriminative stimulus effects will provide a measure of the private experience of withdrawal. Medications will be examined for their ability to modify not only discriminative stimulus effects but also other signs of withdrawal including head shaking and increased night activity in the home cage (i.e. sleep disruption). Aim 1 will examine modification of cannabinoid withdrawal by Δ9-tetrahydrocannabionol alone and in combination with α2-adrenergic agonists (clonidine and lofexidine). The combination has been reported to attenuate marijuana withdrawal more effectively than either drug alone. Quantitative pharmacologic (i.e. isobolographic) analysis will be used to examine whether attenuation of cannabinoid withdrawal by the drug combination is additive, less than additive, or greater than additive (synergistic). Synergistic drug combinations could be especially effective therapeutics. Aim 2 evaluates pharmacotherapy of sleep disruption as a strategy for attenuating cannabinoid withdrawal indexed by discriminative stimulus effects and head shaking during the day. Drugs to be studied for their capacity to attenuate sleep disruption as well as next-day expression of cannabinoid withdrawal signs will include a benzodiazepine (zolpidem or Ambien), the 5HT2A antagonist M100907, and the melatonin agonist ramelteon (Rozerem). Collectively, these specific aims provide a framework for developing novel pharmacotherapies of marijuana withdrawal that could markedly decrease marijuana use and dependence.