Endogenous/exogenous cannabinoids: A comparison

描述（由申请人提供）：自从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）被发现以来，大麻素的研究取得了巨大进展。因此，内源性大麻素信号系统（ECS）可能是大麻“快感”的生物基质。这种主观状态可能是人类大麻消费的基础，可能导致强迫性大麻摄入和依赖障碍。药物鉴别是一种强大的药理学选择模型，用于“主观地”评估动物（和人）经历的药物效应，是该应用中主要的体内行为技术。大麻素受体CB1 （CB1R）激动剂和拮抗剂将接受不同剂量的药物鉴别训练，提供不同灵敏度水平的体内试验。这是补充观察研究和时间表控制响应允许深入表征配体。这项研究的一个主要目的是确定新的药物，将转化为更好的药物治疗，以对抗大麻成瘾。减轻的

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.