Endocannabinoid Discrimination

内源性大麻素歧视

• 批准号: 8312603
• 负责人: JENNY L. WILEY
• 金额: $ 30.38万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312603
• 关键词: 2-arachidonylglycerol; Accounting; Addictive Behavior; Animal Model; Appetite Regulation; Area; Behavior; Behavior Control; Behavioral; Binge Eating; Brain; Brain region; CNR1 gene; CNS processing; Cannabinoids; Cells; Cognition; Conditioned Stimulus; Cues; Data; Development; Discrimination; Drug Kinetics; Eating Disorders; Electric Stimulation; Endocannabinoids; Enzymes; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Proteins; Health; Human; Individual; Knowledge; Lead; Ligands; Lipids; Marijuana Abuse; Measures; Mental disorders; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Mus; Nature; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Play; Procedures; Process; Psychotropic Drugs; Relative (related person); Research; Rewards; Rodent; Role; Self Administration; Self Stimulation; Signal Pathway; Signal Transduction; Stimulus; Substance abuse problem; System; Tetrahydrocannabinol; Therapeutic; Therapeutic Agents; Therapeutic Uses; Tissues; Training; Variant; Work; analog; anandamide; base; behavioral pharmacology; drug discrimination; drug of abuse; genetic manipulation; in vivo; inhibitor/antagonist; insight; interest; mouse model; novel; pleasure; preference; protein activation; public health relevance; receptor; receptor function; reinforcer; response; reward processing; substance abuse treatment; tool

DESCRIPTION (provided by applicant): The endocannabinoid (eCB) system is one of several lipid signaling systems in the brain and in the body. Verified components of this system include two G-protein coupled receptors, their signaling pathways, two predominant endogenous ligands [anandamide (AEA) and 2-arachidonyl glycerol (2-AG)], and their synthetic and metabolic pathways. The system plays an important modulatory role in many crucial CNS processes (e.g., brain reward, appetite regulation, cognition). Consequently, it is not surprising that this system has been implicated in the pathophysiology of a variety of health problems related to these processes, including substance abuse, eating disorders, other types of addictive behavior, and psychiatric disorders. Although research in cells or tissues suggest that there are differences between AEA and 2-AG, examination of potential behavioral consequences of these differences is sparse. Yet, the health problems, for which dysregulation of eCBs in the CNS is most strongly implicated, are problems in which behavior is central. Hence, one of the first steps towards delineation of physiological role(s) that AEA and/or 2-AG may play in health problems such as substance abuse is to distinguish similarities and differences in effects of these two eCBs in pharmacologically selective and validated behavioral procedures relevant to cannabinoid abuse. To this end, two mouse models, drug discrimination and intracranial self-stimulation (ICSS), will be used (Aims 1 and 2). Drug discrimination is an animal model of the subjective effects of psychoactive drugs in humans whereas ICSS represents a method used to evaluate the effects of drugs and behavioral or genetic manipulations on brain reward processes. Each of these factors is known to play a strong role in substance abuse. In addition, brain reward processes undoubtedly are involved in other forms of addictive behavior such as binge eating. The primary guiding idea underlying the proposed studies is that finer distinctions among functions of individual eCBs will be facilitated by knowing the extent to which their behavioral endpoints differ. Further, selected pharmacodynamic mechanisms that may be responsible for differences in the behavioral profiles of these eCBs will be examined (Aim 3). Namely, the relative efficacies and potencies of AEA and 2-AG at a level signal transduction that is a proximal to the ligand-receptor interaction (G-protein activation) will be determined, as the nature of this interaction is associated with alterations in behavioral responses. Results of the proposed studies will enhance understanding of how the eCB system (and especially each of the two major eCBs, AEA and 2-AG) is involved in physiological and pathophysiological processes related to substance abuse. This knowledge, combined with the current rapid development of pharmacological tools to manipulate this system (e.g., inhibitors of eCB synthesis and metabolism), also has the potential to lead to more effective therapeutic agents for health problems related to dysregulation of the eCB system. PUBLIC HEALTH RELEVANCE: Anandamide (AEA) and 2-arachidonyl glycerol (2-AG), the two primary endocannabinoids, play an important modulatory role in many crucial CNS processes such as brain reward, appetite regulation, and cognition. Previous research suggests that dysregulation of the endocannabinoid system is one of the mechanisms involved in substance abuse. Distinguishing the individual roles of AEA and 2-AG in processes related to substance abuse (i.e., subjective effects and brain reward), as is proposed in this project, has the potential to increase understanding of the physiological role(s) of the endocannabinoid system and to serve as a basis for rational choice of pharmacological tools to manipulate this system for therapeutic purposes.

描述（由申请人提供）：内源性大麻素（ECB）系统是大脑和体内的几种脂质信号系统之一。该系统的经过验证的组件包括两个G蛋白偶联受体，其信号通路，两个主要的内源配体[Anandamide（AEA）和2-芳基多酰基甘油（2-AG）]以及其合成和代谢途径。该系统在许多关键的中枢神经系统过程中起重要的调节作用（例如，大脑奖励，食欲调节，认知）。因此，毫不奇怪，该系统已与与这些过程有关的各种健康问题的病理生理学牵涉，包括药物滥用，饮食失调，其他类型的成瘾行为和精神疾病。尽管对细胞或组织的研究表明AEA和2 AG之间存在差异，但这些差异的潜在行为后果的检查很少。然而，在中枢神经系统中，ECB失调的健康问题是最核心的问题。因此，AEA和/或2AG可能在诸如药物滥用之类的健康问题中起作用的生理作用的第一步之一是区分这两种ECB在药理学选择性和验证的与大麻素滥用相关的药理选择性和验证的行为过程中的相似性和差异。为此，将使用两个小鼠模型，药物歧视和颅内自刺激（ICS）（目标1和2）。药物歧视是精神活性药物对人类主观影响的动物模型，而ICS表示一种用于评估药物以及行为或遗传操作对脑奖励过程的影响的方法。众所周知，这些因素中的每一个都在药物滥用中起着重要作用。此外，毫无疑问，大脑奖励过程涉及其他形式的成瘾行为，例如暴饮暴食。提出的研究基础的主要指导思想是，通过了解其行为终点的不同程度，可以促进单个ECB功能之间的更细微的区别。此外，将检查可能导致这些ECB的行为概况差异的选定药效机制（AIM 3）。也就是说，在水平信号转导下，AEA和2AG的相对效率和功效将确定与配体 - 受体相互作用（G蛋白激活）的接近，因为这种相互作用的性质与行为反应的改变有关。拟议的研究的结果将增强对欧洲央行系统（尤其是两个主要ECB，AEA和2AG）如何参与与药物滥用有关的生理和病理生理过程。这些知识以及当前的药理学工具的快速开发来操纵该系统（例如，欧洲央行合成和代谢的抑制剂），也有可能导致更有效的治疗剂，以解决与欧洲央行系统失调有关的健康问题。 公共卫生相关性：两种主要的内源性大麻素的主要内源性大麻素在许多重要的中枢神经系统过程中起着重要的调节作用，例如大脑奖励，食欲调节和认知。先前的研究表明，内源性大麻素系统的失调是滥用药物的机制之一。如本项目所提出的那样，区分AEA和2-AG在与药物滥用有关的过程（即主观效果和大脑奖励）中的各个角色，有可能增加对内源性大麻素系统的生理作用的理解，并有助于作为处理该系统的治疗方法的合理选择的基础。