EtOH Seeking and Relapse: Therapeutic Potential of Transdermal Cannabidiol

成功治疗酒精中毒的一个主要挑战是长期易复发。几个 在禁欲期间恢复饮酒的强迫过程与此有牵连。这些措施包括 酒精(Etoh)相关环境线索或背景产生的饮酒冲动，Etoh诱导 神经适应导致焦虑和压力超敏，以及与以下方面相关的认知缺陷 乙醇诱导的神经变性，可导致冲动控制受损。因此，考虑到各种 存在导致酗酒者易受伤害状态的危险因素，旨在治疗药物发现的方法 为多种诱发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。具有与多个复发漏洞相关的新兴操作配置文件的代理 国家是大麻二酚(CBD)，这是大麻的主要非精神活性和非成瘾成分 种。限制CBD治疗潜力的一个因素是该药物的口服生物利用度较低 缺乏一种现成的、合适的给药方法。然而，有证据表明， 经皮给药途径为CBD提供了一种有效的给药途径。因此， 对经皮CBD(TCBD)作用的临床前评估是及时的，将填补一项重大空白 关于CBD临床潜力的知识。初步研究证实，tCBD可以改善几个方面 与复发风险相关的脆弱性状态，通过线索和压力诱导的衰减来衡量 恢复酒精寻求、焦虑样行为和逆转酒精中毒后的冲动行为 喝醉了。特别重要的是，研究发现，寻求Etoh的减少仍然没有减弱 在近五个月的治疗后测试期结束时。这一观察结果，再加上大气中的 乙醇诱导的冲动是药物开发和神经生物学研究的重要课题。 它暗示了CBD的神经调节作用，可以恢复电路的正常功能 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对与以下各项相关的多个脆弱状态具有治疗潜力的假设 复发风险。这将使用有乙醇依赖史的大鼠来完成，这种状态对 提供翻译相关性，如下所示：通过建立tCBD行动的短期和长期概况 (1)关于强迫性酒精寻求和复发；(2)关于戒断后负性情绪的表现。 通过焦虑样行为和对压力挑战的敏感度来衡量，以及(3)冲动控制受损 由酒精中毒产生。一个平行的目标是确定神经药物系统调节 TCBD的不同行为效应以及tCBD是否具有神经保护作用或神经源性作用 与预防或逆转受损的冲动控制有关的行动。结果很可能会有 对于治疗药物开发和了解复发的神经基础具有重要意义。

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.