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: 7687060
• 负责人: Lance R McMahon
• 金额: $ 34.68万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687060
• 关键词: Abstinence; Address; Adrenergic Agonists; Agonist; Attenuated; Benzodiazepines; Biological Assay; Budgets; Cannabinoids; Cannabis-Related Disorder; Chronic; Clinical; Clinical assessments; Clonidine; Dependence; Development; Drug Combinations; Effectiveness; Grant; Head; Home environment; Human; Individual; Laboratories; Laboratory Study; Macaca mulatta; Marijuana; Marijuana Dependence; Marijuana Smoking; Measures; Melatonin; Modification; Monkeys; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Public Health; Relapse; Reporting; Sanofi brand of zolpidem tartrate; Sleep; Stimulus; Substance Withdrawal Syndrome; Sum; Testing; Tetrahydrocannabinol; Therapeutic; Withdrawal; attenuation; base; craving; drug testing; experience; indexing; lofexidine; marijuana user; nonhuman primate; novel; pre-clinical; preclinical study; response; rimonabant; 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（大麻相关疾病的药物开发）而提交的，已进行修改以适应 2 年预算，该赠款建议在非人类中使用大麻素戒断的临床前措施。灵长类动物以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，大麻戒断的药物治疗与大麻戒断有关。因此，该应用减少了对临床前检测的迫切需求，该检测可以提供快速有效的药物减弱大麻素戒断能力的测试。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，大麻素主要负责大麻的滥用和依赖倾向，将提供区分性刺激作用。将检查药物不仅能改变歧视性刺激效应，还能改变其他戒断症状，​​包括摇头和在家笼子里夜间活动增加（即睡眠中断）。单独使用 Δ9-四氢大麻酚以及与 α2-肾上腺素能激动剂（可乐定和洛非西定）联合使用可减少大麻素戒断，据报道，该组合比任何一种药物都更有效地减少大麻戒断。定量药理学（即等辐射）分析将用于检查药物组合对大麻素戒断的减弱是否是累加性、小于累加性或大于累加性（协同作用）。目标 2。评估睡眠中断的药物疗法作为减轻大麻素戒断的策略，以区分性刺激作用和白天摇头药物的能力为指标。减轻睡眠干扰以及第二天大麻素戒断症状的表现将包括苯二氮卓类药物（唑吡坦或 Ambien）、5HT2A 拮抗剂 M100907 和褪黑激素激动剂雷美替胺（Rozerem）。总的来说，这些具体目标为开发新型药物疗法提供了框架。大麻戒断可能会显着减少大麻的使用和依赖。