EtOH Seeking and Relapse: Therapeutic Potential of Transdermal Cannabidiol

乙醇寻找和复发：透皮大麻二酚的治疗潜力

基本信息

批准号：
9011983
负责人：
Friedbert Weiss
金额：
$ 36.43万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9011983
关键词：
Abstinence Address Aftercare Alcoholic Intoxication Animal Model Anxiety Application procedure Attenuated Behavior Behavioral Biological Availability Brain Cannabidiol Cannabis sativa plant Chronic Clinical Cognitive deficits Consumption Cues Data Dependence Dependency Development Dose Drug Delivery Systems Employee Strikes Ethanol Evaluation Exposure to FDA approved Future Goals Health Hypersensitivity Impulsive Behavior Impulsivity Incentives Knowledge Lead Link Measures Mediating Methods Motivation Nerve Degeneration Neurobiology Oral Pharmaceutical Preparations Pharmacotherapy Pre-Clinical Model Precipitating Factors Predisposition Prevention Process Property Rattus Recording of previous events Relapse Research Rewards Risk Factors Route Site Stress Substance Addiction System Testing Therapeutic Time Withdrawal addiction alcoholism therapy anxiety-like behavior attenuation base compulsion conditioning craving disorder later incidence prevention drinking drug development drug discovery factor A improved interest man negative affect neuroadaptation neurobehavioral preclinical evaluation prevent problem drinker relapse risk relating to nervous system responsible alcohol use sedative targeted treatment transdermal cannabidiol treatment effect

项目摘要

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.

描述（由申请人提供）：成功治疗酒精中毒的主要挑战是持久的复发敏感性。在戒酒期间恢复饮酒的强迫涉及几个过程。其中包括由乙醇（ETOH）相关的环境线索或环境产生的饮酒冲动，ETOH诱导的神经适应性导致焦虑和对压力过敏，以及与EtOH诱导的神经变性相关的认知缺陷，这可能导致受损的脉冲控制。因此，考虑到存在各种危险因素，这些风险因素引起了酗酒者的脆弱性状态，因此旨在为多种造成促成因素提供保护的调节药物发现方法可能比仅针对单个因素的方法更有效。具有与多重复发脆弱性状态相关的动作概况的代理是大麻二酚（CBD），这是大麻sativa植物的主要非精神活性和非添加性成分。限制CBD在人类中的治疗潜力的因素是该药物的低口服生物利用度，缺乏容易获得且合适的药物输送方法。但是，有证据表明，透皮管理途径为CBD提供了有效的输送方法。因此，对透皮CBD（TCBD）作用概况的临床前评估是及时的，并且将弥补有关CBD临床潜力的知识的主要差距。初步研究证实，TCBD可以通过衰减ETOH侵入后的ETOH寻求，焦虑行为以及脉冲行为的逆转来缓解与复发风险相关的几个脆弱状态。特别重要的是，在接近五个月的治疗测试期结束时，寻求ETOH的减少仍未减弱。从药物开发和神经生物学的角度来看，这种观察结果与ETOH诱导的冲动性的衰减相结合，具有重大的兴趣，因为它暗示了CBD的神经调节作用，该动作恢复了调节循环奖励的正常功能，从而调节奖励，激励性动机，冲动，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，压力，强度和焦虑。该项目的目的是确认TCBD具有与复发风险相关的多个漏洞状态的治疗潜力的假设。这将完成使用具有ETOH依赖史的大鼠，这是提供翻译相关性至关重要的状态，如下所示：通过建立TCBD动作的短期和长期形象（1）对强迫性ETOH寻求和复发的态度，（2）对焦虑行为和敏感性挑战的敏感性和（3）对IMPAIR的敏感性对影响的负面影响，以及对IMPAIRS的敏感性，以及对Impairs的敏感性进行了衡量。一个平行的目标是确定介导TCBD的不同行为效应的神经药物系统，并检查TCBD是否具有与预防或反转脉冲控制受损相关的神经保护作用或倾斜性作用。结果可能具有重大影响，即治疗药物开发和对复发神经基础的理解。