Pharmacotherapy of Cannabinoid Withdrawal: Pre-Clinical Studies

为响应RFA-DA-09-001（大麻相关疾病的药物开发）而提交的本R 01已进行修改，以适应2年预算。该拨款建议使用非人类灵长类动物大麻素戒断的临床前措施来确定大麻依赖的潜在药物治疗。超过一半的日常大麻使用者在停止使用后会经历戒断，据报道这会导致大麻吸食。大麻戒断的药物治疗与临床实验室中大麻使用的复发减少有关，因此，是促进禁欲的可行策略。本申请解决了对临床前测定的迫切需要，所述临床前测定可以提供药物的快速和有效的测试，以确定其减弱大麻素戒断的能力。大麻素拮抗剂利莫那班将为接受Δ9-四氢大麻酚长期治疗的恒河猴提供戒断指数，Δ9-四氢大麻酚是主要导致大麻滥用和依赖倾向的大麻素。区别性刺激效应将提供一个衡量个人退缩经验的尺度。将检查药物不仅改变辨别性刺激效应的能力，还改变其他戒断体征的能力，包括摇头和笼舍夜间活动增加（即睡眠中断）。目的1将检查单独的Δ9-四氢大麻酚和与α2-肾上腺素能激动剂（可乐定和洛非西定）组合对大麻素戒断的改变。据报道，这种组合比单独使用任何一种药物都能更有效地减少大麻戒断。将使用定量药理学（即等效线）分析来检查药物组合对大麻素戒断的衰减是否是相加的、小于相加的或大于相加的（协同的）。协同药物组合可能是特别有效的治疗方法。目的2评估药物治疗的睡眠中断作为一种策略，用于衰减大麻素戒断指数的歧视性刺激效应和摇头在白天。研究药物减轻睡眠中断以及第二天大麻素戒断症状表达的能力将包括苯二氮卓类（唑吡坦或安必恩）、5 HT 2A拮抗剂M100907和褪黑激素激动剂雷美替酮（Rozerem）。总的来说，这些具体目标为开发大麻戒断的新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.