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 在戒酒期间恢复饮酒的强迫性过程中有牵连。这些包括 由乙醇（EtOH）相关的环境线索或背景产生的饮酒冲动，EtOH诱导的 神经适应导致焦虑和对压力的超敏反应，以及与 EtOH诱导的神经变性可导致冲动控制受损。考虑到各种 存在引起酗酒者脆弱状态的风险因素，治疗药物发现的方法旨在 为多种诱发因素提供保护可能比针对 只有一个因素。一种具有与多重复发脆弱性相关的新兴作用特征的药物 大麻二酚（CBD）是大麻的主要非精神活性和非成瘾成分 厂限制CBD对人类治疗潜力的一个因素是该药物的口服生物利用度低， 缺乏容易获得和合适的药物递送方法。然而，有证据表明， 经皮给药途径为CBD提供了有效的递送方法。因此，我们认为， 对经皮CBD（tCBD）的作用特征进行临床前评价是及时的，将填补一个主要空白 CBD的临床潜力。初步研究证实，tCBD改善了几个 脆弱性状态与复发风险相关，通过线索和压力诱导的 EtOH寻求、焦虑样行为和EtOH后冲动行为逆转的恢复 中毒特别重要的是发现乙醇寻求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，与衰减的 乙醇诱导的冲动，是从药物开发和神经生物学的实质性利益 这表明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。该项目的目的是 证实了这一假设，即tCBD对与以下疾病相关的多种脆弱性状态具有治疗潜力： 复发风险这将使用具有EtOH依赖史的大鼠来完成，这是一种对 通过建立tCBD行动的短期和长期概况， (1)对强迫性乙醇寻求和复发，（2）对戒断后表现的负面影响， 通过焦虑样行为和对压力挑战的敏感性来测量，以及（3）对受损的冲动控制 由乙醇中毒引起的一个平行的目标是确定神经药理学系统介导 tCBD的不同行为效应，并检查tCBD是否具有神经保护或神经原性 与预防或逆转受损的冲动控制相关的行动。结果很可能是 对治疗药物开发和理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.