EtOH Seeking and Relapse: Therapeutic Potential of Transdermal Cannabidiol

描述(由申请人提供)：成功治疗酒精中毒的一个主要挑战是长期易复发。在禁欲期间，有几个过程与恢复饮酒的强迫有关。这些包括与乙醇(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高敏感性，以及与Etoh诱导的神经退化相关的认知缺陷，后者可能导致冲动控制受损。因此，考虑到存在导致酗酒者处于脆弱状态的各种风险因素，旨在为多种诱发因素提供保护的药物发现治疗方法可能比仅针对单一因素的方法更有效。大麻二酚(CBD)是一种新出现的与多种易复吸状态有关的行动概况，它是大麻植物的主要非精神活性和非成瘾成分。限制CBD在人体内治疗潜力的一个因素是该药物的口服生物利用度低，加上缺乏容易获得和合适的药物输送方法。然而，已有证据表明，经皮给药途径为CBD提供了一种有效的给药方法。因此，对经皮CBD(TCBD)作用模式的临床前评估是及时的，并将填补关于CBD临床潜力的一个主要认识空白。初步研究证实，tCBD改善了与复发风险相关的几种脆弱状态，通过线索和压力诱导的乙醇寻求、焦虑样行为和乙醇中毒后冲动行为的逆转的减弱来衡量。特别重要的是，研究发现，在近五个月的治疗后试验期结束时，寻求乙醇的减少仍然没有减少。这种观察，加上乙醇诱导的冲动减弱，从药物开发和神经生物学角度都很有意义，因为它暗示了CBD的神经调节作用，使调节奖赏、激励动机、冲动和压力的回路恢复正常功能。 和焦虑。该项目的目的是确认这样一个假设，即tCBD对与复发风险相关的多种脆弱状态具有治疗潜力。这将会实现的 使用有乙醇依赖史的大鼠，这一状态对于提供翻译相关性至关重要，如下：通过建立tCBD行动的短期和长期概况：(1)关于强迫性寻求和复发，(2)关于戒断后负面情绪的表现，通过焦虑样行为和对压力挑战的敏感性来衡量，以及(3)关于酒精中毒所产生的冲动控制受损。一个平行的目标是确定神经药理系统调节tCBD的不同行为效应，并检查tCBD是否具有神经保护或神经原作用，与预防或逆转受损的冲动控制有关。这一结果可能对治疗、药物开发和了解复发的神经基础具有重要意义。

DESCRIPTION (provided by applicant): 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 treatent 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 fo treatment drug development and understanding of the neural basis of relapse.