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。在戒酒期间恢复饮酒的强迫行为牵涉到几个过程。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诱导的神经变性相关的认知缺陷，这可能导致冲动控制受损。因此，考虑到引发酗酒者脆弱状态的各种风险因素的存在，旨在为多种诱发因素提供保护的治疗药物发现方法可能比仅针对单一因素的方法更有效。大麻二酚（CBD）是一种与多重复发易感状态相关的新兴行为，它是大麻植物的主要非精神活性和非成瘾成分。限制CBD在人类治疗潜力的一个因素是该药物的低口服生物利用度以及缺乏现成和合适的给药方法。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方法。因此，对透皮CBD （tCBD）的作用谱进行临床前评估是及时的，并将填补CBD临床潜力方面的重大空白。初步研究证实，tCBD改善了与复发风险相关的几种脆弱性状态，通过减弱线索和压力诱导的EtOH寻求恢复、焦虑样行为和EtOH中毒后冲动行为的逆转来测量。特别重要的是，在治疗后近五个月的测试期结束时，寻求EtOH的人数仍然没有减少。从药物开发和神经生物学的角度来看，这一观察结果与etoh诱导的冲动性减弱相结合，具有重大的意义，因为它表明CBD的神经调节作用可以恢复调节奖励、激励动机、冲动性和压力的神经回路的正常功能

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.