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.

该R01是针对RFA-DA-09-001（与大麻相关疾病的药物开发）提交的，已修改以适应2年的预算。使用非人类隐私的大麻素戒断前临时措施的赠款提案，以识别大麻依赖性的潜在药物治疗。超过一半的每日大麻使用者在停用使用后会撤离，这据报道会吸引大麻吸烟。大麻戒断的药物疗法与临床实验室中大麻使用的继电器改善有关，因此是促进禁欲的可行策略。该应用程序解决了对临床前测定的迫切需求，该测定方法可以为药物降低大麻素的能力提供快速有效的药物测试。大麻素拮抗剂Rimonabant将在接受Δ9-四氢大麻酚的慢性治疗的恒河猴中提供戒断的指数，这是大麻素的主要主要负责大麻的滥用和依赖性责任。歧视性刺激效应将提供一定程度的撤回私人经验。将检查药物的能力，不仅可以修改判别性刺激效果，还可以检查其他戒断迹象，包括头部摇动和增加家庭笼子中的夜间活动（即睡眠破坏）。 AIM 1将检查单独使用Δ9-四氢大麻酚对大麻素戒断的修饰，并与α2-肾上腺素能激动剂（可乐定和洛芬己定）结合使用。据报道，该组合比单独使用任何一种药物更有效地减弱大麻戒断。定量药理学（即同胞）分析将用于检查药物组合戒断大麻素的衰减是否是添加剂，小于添加剂或大于添加剂（协同作用）。协同药物组合可能是特别有效的治疗。 AIM 2评估睡眠中断的药物治疗是减弱大麻素戒断的策略，该策略在白天通过歧视性刺激效应和头部颤抖。衰减睡眠破坏的能力以及大麻素戒断迹象的次日表达的药物将包括苯二氮卓类药物（Zolpidem或Ambien），5HT2A拮抗剂M100907，以及褪黑激素的Ramelteon（Rozerem）。总的来说，这些特定的目标为开发新型大麻戒断药物治疗提供了一个框架，这些药物本来可以显着减少大麻的使用和依赖性。