EtOH Seeking and Relapse: Therapeutic Potential of Transdermal Cannabidiol

乙醇寻找和复发：透皮大麻二酚的治疗潜力

• 批准号: 8624288
• 负责人: Friedbert Weiss
• 金额: $ 38.23万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624288
• 关键词: A-factor (Streptomyces); Abstinence; Address; Affect; Aftercare; Alcoholic Intoxication; Animal Model; Anxiety; Application procedure; Attenuated; Behavior; Behavioral; Biological Availability; Brain; Cannabidiol; Cannabis sativa plant; Chronic; Clinical; Cognitive deficits; Consumption; Cues; Data; Dependence; Dependency; Development; Dose; Drug Delivery Systems; Drug Targeting; Employee Strikes; Ethanol; Evaluation; Exposure to; FDA approved; Future; Goals; Hypersensitivity; Impulsive Behavior; Impulsivity; Incentives; Knowledge; Lead; Link; Measures; Mediating; Methods; Motivation; Nerve Degeneration; Neurobiology; Oral; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Precipitating Factors; Predisposition; Prevention; Process; Property; Rattus; Recording of previous events; Relapse; Research; Rewards; Risk; Risk Factors; Route; Site; Stress; Substance Addiction; System; Testing; Therapeutic; Time; Withdrawal; addiction; alcoholism therapy; attenuation; base; conditioning; craving; disorder later incidence prevention; drinking; drug development; drug discovery; improved; interest; man; neuroadaptation; neurobehavioral; preclinical evaluation; prevent; problem drinker; public health relevance; relating to nervous system; responsible alcohol use; sedative; treatment effect

A major challenge for the successful treatment of alcoholism is long-lasting susceptibility to relapse. Several processes have been implicated in the compulsion to resume drinking during abstinence. These include drinking urges produced by ethanol (EtOH)-related environmental cues or contexts, EtOH-induced neuroadaptation resulting in anxiety and hypersensitivity to stress, as well as cognitive deficits associated with EtOH-induced neurodegeneration that can lead to impaired impulse control. Thus, considering that various risk factors exist that elicit vulnerability states in alcoholics, approaches to treatment drug discovery aimed at providing protection for multiple precipitating factors are likely to be more effective than approaches targeting only a single factor. An agent with an emerging profile of actions relevant for multiple relapse vulnerability states is cannabidiol (CBD), the main non-psychoactive and non-addictive component of the cannabis sativa plant. A factor limiting CBD's therapeutic potential in man has been the drug's low oral bioavailability paired with lack of a readily available and suitable drug delivery method. However, evidence has become available that the transdermal route of administration provides an effective delivery method for CBD. Therefore, preclinical evaluation of the profile of actions of transdermal CBD (tCBD) is timely and will close a major gap in knowledge on CBD's clinical potential. Preliminary studies confirmed that tCBD ameliorates several vulnerability states associated with relapse risk as measured by attenuation of cue- and stress-induced reinstatement of EtOH seeking, anxiety-like behavior, and reversal of impulsive behavior following EtOH intoxication. Of particular significance was the finding that the reduction of EtOH seeking remained unabated at the end of a nearly five-month post-treatment test period. This observation, paired with the attenuation of EtOH-induced impulsivity, is of substantial interest from both a medication development and neurobiological perspective in that it is suggestive of neuroregulatory actions of CBD that restore normal function to circuitries regulating reward, incentive motivation, impulsivity, stress and anxiety. The purpose of this project is to confirm the hypothesis that tCBD has therapeutic potential for multiple vulnerability states associated with relapse risk. This will be accomplished using rats with a history of EtOH dependence, a status essential for providing translational relevance, as follows: By establishing the short- and long-term profile of tCBD actions (1) on compulsive EtOH seeking and relapse, (2) on post-withdrawal manifestations of negative affect as measured by anxiety-like behavior and sensitivity to stress challenges, and (3) on impaired impulse control produced by EtOH intoxication. A parallel objective is to identify neuropharmacological systems mediating the diverse behavioral effects of tCBD and to examine whether tCBD has neuroprotective or proneurogenic actions relevant for the prevention or reversal of impaired impulse control. The results are likely to have significant implications for treatment drug development and understanding of the neural basis of relapse.

成功治疗酒精中毒的主要挑战是对复发的持久敏感性。一些 在禁欲期间恢复饮酒的强迫症与过程有关。这些包括 乙醇（ETOH）相关的环境提示或环境，ETOH诱导的饮酒冲动 神经适应导致压力的焦虑和过敏，以及与之相关的认知缺陷 EtOH诱导的神经退行性变成可能导致脉冲控制受损。因此，考虑到各种 存在引起酗酒者脆弱状态的危险因素，针对治疗药物发现的方法 为多种造成因素提供保护可能比针对目标的方法更有效 只有一个因素。具有与多重复发脆弱性相关的动作概况的代理商 状态是大麻sativa的主要非精神活性和非添加成分的大麻二醇（CBD） 植物。限制CBD在人类中的治疗潜力的因素是该药物的低口服生物利用度配对 由于缺乏易于可用且合适的药物输送方法。但是，证据已被可用 透皮管理途径为CBD提供了有效的输送方法。所以， 对透皮CBD（TCBD）动作概况的临床前评估是及时的，将缩小主要差距 关于CBD临床潜力的知识。初步研究证实，TCBD可以改善几个 与提示和压力引起的衰减相关的脆弱状态与复发风险相关 恢复ETOH寻求ETOH，焦虑般的行为以及ETOH后冲动行为的逆转 中毒。特别重要的是发现，寻求EtoH的减少仍然没有减弱 在经过近五个月的治疗测试期结束时。这个观察结果与 EtOH引起的冲动性，从药物开发和神经生物学中具有很大的兴趣 观点是，它暗示了CBD的神经调节作用，使电路正常功能恢复正常功能 调节奖励，激励动机，冲动，压力和焦虑。这个项目的目的是 确认TCBD具有与与之相关的多个漏洞状态具有治疗潜力的假设 复发风险。这将使用具有ETOH依赖史的老鼠来实现，这是对 提供翻译相关性，如下：建立TCBD动作的短期和长期概况 （1）关于强迫性ETOH寻求和复发，（2）关于负面影响的后绘图后表现形式 通过焦虑般的行为和对压力挑战的敏感性来衡量，（3）冲动控制受损 由EtoH中毒产生。一个平行的目标是识别介导的神经药物系统 TCBD的不同行为效应，并检查TCBD是否具有神经保护作用或促尿液原性 与预防或逆转脉冲控制相关的行动。结果可能有 对治疗药物发展和对复发神经基础的理解的重要意义。