Pharmacotherapy of Cannabinoid Withdrawal: Pre-Clinical Studies

大麻素戒断的药物治疗：临床前研究

• 批准号: 7876875
• 负责人: Lance R McMahon
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876875
• 关键词: Abstinence; Address; Adrenergic Agonists; Agitation; Agonist; Attenuated; Benzodiazepines; Biological Assay; Budgets; Bupropion; Cannabinoids; Cannabis-Related Disorder; Catecholamines; Chronic; Clinical; Clinical Research; Clinical assessments; Clonidine; Dependence; Development; Drug Combinations; Effectiveness; Grant; Head; Home environment; Human; Individual; Laboratories; Laboratory Study; Ligands; Macaca mulatta; Marijuana; Marijuana Dependence; Marijuana Smoking; Measures; Melatonin; Modification; Monkeys; Opioid; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Public Health; Relapse; Reporting; Sanofi brand of zolpidem tartrate; Serotonin; Signal Transduction; Site; Sleep; Sleep disturbances; Stimulus; Sum; Testing; Tetrahydrocannabinol; Therapeutic; Withdrawal; attenuation; base; craving; drug testing; experience; indexing; inhibitor/antagonist; lofexidine; marijuana user; monoamine; nefazodone; nonhuman primate; noradrenergic; novel; pre-clinical; preclinical study; receptor; response; rimonabant; uptake; zolpidem

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.

本R01是根据RFA-DA-09-001(大麻相关疾病的药物开发)提交的，已进行了修改，以适应2年期预算。该赠款建议在非人类灵长类动物中使用临床前的大麻类戒断措施来确定大麻依赖的潜在药物疗法。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，这会导致吸食大麻。大麻戒断的药物治疗与减少临床实验室中使用大麻的复发率有关，因此是促进戒烟的可行策略。这一应用满足了对临床前检测的迫切需要，这种检测能够快速有效地测试药物减轻大麻素戒断的能力。大麻素拮抗剂利莫那班将为接受Δ9-四氢大麻酚长期治疗的恒河猴提供戒断指数，四氢大麻酚是大麻滥用和依赖倾向的主要责任。歧视性刺激效应将提供一种衡量个人戒烟体验的指标。将检查药物不仅能改变歧视性刺激效应，还能改变其他戒断迹象，包括摇头和在家中夜间活动增加(即睡眠中断)。目的1研究Δ-9-四氢大麻硫醇单独以及与α-2-肾上腺素能激动剂(可乐定和洛非西定)联合使用对大麻素戒断的影响。据报道，这两种药物联合使用比单独使用任何一种药物都能更有效地抑制大麻戒断。将使用定量药理学(即等效学)分析来检查药物组合对大麻类戒断的减弱是相加的、小于相加的、还是大于相加的(协同作用)。协同药物组合可能是特别有效的治疗方法。目的2评估睡眠干扰的药物治疗作为一种减轻大麻类药物戒断的策略，该策略以辨别刺激效应和白天摇头为指标。正在研究的药物将包括苯二氮类药物(唑吡坦或安必恩)、5HT2A拮抗剂M100907和褪黑素激动剂Ramelteon(Rozerem)，以了解其减轻睡眠干扰以及第二天表达大麻类戒断迹象的能力。总体而言，这些具体目标为开发可显著减少大麻使用和依赖的大麻戒断新药物疗法提供了一个框架。