Endocannabinoid Discrimination

描述（由申请人提供）：内源性大麻素（eCB）系统是大脑和身体中的几种脂质信号传导系统之一。该系统的验证组件包括两个G蛋白偶联受体，其信号传导途径，两个主要的内源性配体[花生四烯酸酰胺（AEA）和2-花生四烯酸甘油（2-AG）]，以及它们的合成和代谢途径。该系统在许多关键的CNS过程中起着重要的调节作用（例如，大脑奖励、食欲调节、认知）。因此，这并不奇怪，该系统已牵连在与这些过程相关的各种健康问题的病理生理学，包括药物滥用，饮食失调，其他类型的成瘾行为，和精神疾病。虽然在细胞或组织中的研究表明AEA和2-AG之间存在差异，但对这些差异的潜在行为后果的检查很少。然而，CNS中eCB的失调最强烈地牵涉到的健康问题是其中行为是中心的问题。因此，描绘AEA和/或2-AG在药物滥用等健康问题中可能发挥的生理作用的第一步之一是区分这两种eCB在与大麻素滥用相关的药物选择性和经验证的行为程序中的作用的相似性和差异。为此，将使用两种小鼠模型，药物辨别和颅内自刺激（ICSS）（目的1和2）。药物辨别是人类精神活性药物主观效应的动物模型，而ICSS代表了用于评估药物和行为或遗传操纵对大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，大脑的奖赏过程无疑与其他形式的成瘾行为有关，比如暴饮暴食。拟议研究的主要指导思想是，通过了解其行为终点的差异程度，将有助于更好地区分个体eCB的功能。此外，将检查可能导致这些eCB行为特征差异的选定药效学机制（目的3）。也就是说，将确定AEA和2-AG在接近配体-受体相互作用（G蛋白活化）的信号转导水平下的相对功效和效力，因为这种相互作用的性质与行为反应的改变相关。拟议研究的结果将增强对eCB系统（尤其是两种主要eCB，AEA和2-AG）如何参与与药物滥用相关的生理和病理生理过程的理解。这些知识，结合目前快速发展的药理学工具来操纵这个系统（例如，eCB合成和代谢的抑制剂），也有可能导致更有效的治疗剂，用于与eCB系统失调相关的健康问题。 公共卫生相关性：大麻素（Anandamide，AEA）和2-花生四烯酸甘油（2-arachidonyl glycerol，2-AG）是两种主要的内源性大麻素，在许多重要的中枢神经系统过程中发挥重要的调节作用，如大脑奖赏、食欲调节和认知。以前的研究表明，内源性大麻素系统的失调是药物滥用的机制之一。区分AEA和2-AG在与药物滥用有关的过程中的各自作用（即，主观效应和大脑奖赏），有可能增加对内源性大麻素系统生理作用的理解，并作为合理选择药理学工具的基础，为治疗目的操纵这一系统。

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.