Endogenous/exogenous cannabinoids: A comparison

描述(申请人提供)：自从发现大麻中的主要活性成分9-四氢大麻酚(THC)等化学物质的特定识别位点(受体)以来，对大麻类物质的研究取得了巨大进展。因此，内源性大麻素信号系统(ECS)很可能是大麻“兴奋”的生物底物。据推测，这种主观状态是人类吸食大麻的基础，可能会导致强迫性大麻摄入和依赖障碍。药物辨别是一种强大的、药理选择性的模型，用于评估动物(和人类)对药物的“主观”体验效果，也是这一应用中的主要体内行为技术。大麻素受体CB1(CB1R)激动者和拮抗者将接受使用不同剂量的药物识别培训，以提供不同灵敏度水平的体内测试。这与观察性研究和时间表控制的反应相辅相成，允许对配体进行深入的表征。这项研究的一个主要目的是确定新的药物，这些药物将转化为更好的抗击大麻成瘾的药物疗法。缓解 身体依赖个体的戒断相关效应可能是成瘾过程中的一个重要动机因素。新的分子是由现场专业人员设计和合成的。其中一个重点是寻找和提纯体内中性的CB1R拮抗剂。大多数目前的CB1R拮抗剂也表现出内在的活性(反向兴奋)，这可能会阻碍患者在治疗环境中的依从性。因此，这些研究将扩大我们对ECS的理解，ECS由两个主要的内源性信号分子组成，分别作用于两个已知的受体CB1和CB2，在正常的身体功能和病理生理学中作用于两个已知的受体：花生胺(AEA)和2-花生四烯酸甘油(2-AG)。应用的其他“治疗”靶点涉及选择性地影响内源性大麻素失活所涉及的酶的配体，从而潜在地避免直接受体激活。行为研究是由合作教员在追求这些目标的过程中提供的神经/生化程序的辅助。除了AEA，关于2-AG的最新进展使我们能够更全面地了解ECS信号转导中的这种主要内源性大麻素。通过获得内源性物质(AEA和2-AG)和外源性THC以及体内中性阻滞剂的功能信息，这些研究不仅将加深我们对ECS信号在大麻滥用/依赖行为神经生物学中的理解，而且还可能导致开发有效的药物来治疗涉及大麻/大麻的疾病，以及“设计类似THC”的大麻仿制。 公共卫生相关性：美国的一个主要社会关切是成瘾障碍，包括对大麻的依赖。尽管取得了进展，但还没有官方接受的药物治疗来缓解大麻的戒断症状，并在实现初步戒酒后降低复发的可能性。目前研究应用的目标是协助填补这些空白。

DESCRIPTION (provided by applicant): Research on cannabinoids has progressed tremendously since the discovery of specific recognition sites (receptors) for chemicals like ¿9-tetrahydrocannabinol (THC), the main active ingredient in marijuana. The endocannabinoid signaling system (ECS) thus likely serves as the biological substrate for the marijuana "high". This subjective state presumably underlies human marijuana consumption that may lead to compulsive cannabis intake and dependence disorders. Drug discrimination is a powerful, pharmacologically selective model for assessing "subjectively" experienced drug effects in animals (and man) and is the major in vivo behavioral technique in this application. Cannabinoid receptor CB1 (CB1R) agonists and antagonists will be trained in drug discrimination using different doses, providing for in vivo assays with different sensitivity levels. This is complemented by observational studies and schedule controlled responding allowing for an in depth characterization of ligands. A major aim of this research is to identify new medications that will translate into better pharmacotherapies for combating marijuana addiction. Alleviation of withdrawal-related effects in physically dependent individuals likely is an important motivational factor in addiction processes. New molecules are designed and synthesized by on site expertise. One focus is to identify and refine in vivo neutral CB1R antagonists. Most current CB1R antagonists also display intrinsic activity (inverse agonism) that may hamper patient compliance in treatment settings. Thus, the studies will expand our understanding of the ECS, comprised of two major endogenous signaling molecules, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) acting on two known receptors, CB1 and CB2, in normal body function and pathophysiology. Additional "therapeutic" targets for the application concern ligands selectively affecting the enzymes involved in the deactivation of the endocannabinoids, thus potentially avoiding direct receptor activation. The behavioral studies are aided by neuro/biochemical procedures provided by collaborating faculty in pursuing these goals. In addition to AEA, recent developments regarding 2-AG allow for a much more comprehensive understanding of this major endocannabinoid in ECS signaling. By obtaining information on the functions of the endogenous substances (AEA and 2-AG) and the exogenous THC, as well as in vivo neutral blocking agents, these studies will not only further our understanding of ECS signaling in the behavioral neurobiology of cannabis abuse / dependence, but may also lead to the development of effective medications for treating disorders involving cannabis / marijuana, and "designer THC-like" cannabimimetics. PUBLIC HEALTH RELEVANCE: A major societal concern in the United States is addiction disorders, including cannabis dependence. Although progress has been made, there are no officially accepted pharmaceutical treatments to alleviate marijuana withdrawal symptoms and to reduce the likelihood of relapse once initial sobriety has been achieved. The goals of the current research application are aimed at assisting in filling those gaps.