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，强迫性恢复饮酒涉及到几个过程。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，考虑到存在各种风险因素，引起酗酒者的脆弱性状态，方法，以提供保护的多个促发因素的自发药物发现可能是更有效的方法，只针对一个单一的因素。一种与多重复发脆弱性状态相关的新出现的行动概况的代理人是大麻二酚（CBD），大麻植物的主要非精神活性和非成瘾成分。限制CBD在人类中的治疗潜力的一个因素是该药物的口服生物利用度低，缺乏现成的合适的药物递送方法。然而，已有证据表明，经皮给药途径为CBD提供了有效的递送方法。因此，对经皮CBD（tCBD）的作用特征进行临床前评价是及时的，将填补CBD临床潜力知识的主要空白。初步研究证实，tCBD改善与复发风险相关的几种脆弱性状态，如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，在近5个月的治疗后测试期结束时，EtOH寻求的减少仍然没有减弱。这一观察结果与EtOH诱导的冲动的衰减相结合，从药物开发和神经生物学的角度来看都具有重大意义，因为它表明CBD的神经调节作用恢复了调节奖励，激励动机，冲动，压力的电路的正常功能。 和焦虑该项目的目的是证实tCBD对与复发风险相关的多种脆弱性状态具有治疗潜力的假设。这将是完成 使用具有EtOH依赖史的大鼠，这是提供翻译相关性所必需的状态，如下：通过建立tCBD作用的短期和长期概况（1）对强迫性EtOH寻求和复发，（2）对如通过焦虑样行为和对压力挑战的敏感性测量的负面影响的戒断后表现，和（3）对由EtOH中毒产生的受损的冲动控制。一个平行的目标是确定神经药理学系统介导的不同行为效应的tCBD和检查是否tCBD有神经保护或proneurogenic行动相关的预防或逆转受损的冲动控制。这些结果可能对治疗药物的开发和对复发的神经基础的理解有重要意义。

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.