A novel cannabinoid receptor in cortical nerve terminals

说明(申请人提供)：大麻是最广泛使用的精神药物之一，它与许多严重的不良反应有关，包括依赖、精神障碍和心肺疾病。详细了解这种药物的作用机制对于了解其许多作用至关重要，并可能极大地有助于药物的设计，以促进大麻依赖和戒断的治疗。识别所有的大麻素受体是这个问题的核心。除了两个特性良好的经典大麻素受体外，最近还发现了另外三个受体。根据其在大脑中的分布和功能，也有人认为细胞外钙感受器(CaSR)将是大麻类药物的合适靶点。在初步实验中，我们发现大麻类化合物激活了CaSR，这是一种G蛋白偶联受体(GPCR)，定位于大脑中大多数神经末梢，并在激活时减少突触传递。这些初步发现，再加上大脑中丰富的CaSR，可能会从根本上改变我们对大麻类物质作用机制的理解。这项提议的目的是确定CaSR是否是大麻类药物作用的重要途径，我们的假设是大脑CaSR直接被大麻类化合物激活。我们非常适合执行这个项目，因为我们在神经末梢和表达系统的CaSR功能方面的专业知识。CaSR对大麻素的敏感性和大脑中CaSR的流行将打开对大麻类药物作用的新视角，极大地改变这一领域的思维。这些具体目标的成功完成将是CASR对大麻素的反应的特征，有助于了解CASR的更广泛的影响范围。这项工作将定义必要的工具，以剖析CaSR和CB1对大麻素调节大脑中突触传递的相对贡献。未来的提案将结合药理学和遗传学方法，通过中央突触的CB1和CaSR来确定大麻类化合物的影响。我们的理论基础是，一种新的和流行的大麻素受体的鉴定和表征将有助于我们了解常用药物大麻的行为行为。此外，区分大麻素的各种作用可转化为确定一类有助于治疗大麻成瘾和戒断的新型药物。 公共卫生相关性：大麻是一种常用药物，与药物依赖以及严重的精神、心血管和肺部疾病有关。需要新的治疗方法来帮助人们停止使用大麻，但这需要更好地了解大麻的作用方式。我们已经在大脑中发现了一条新的通路，这条通路可以被大麻类药物激活。通过研究这一新途径，我们将发现更多关于大麻如何发挥作用的信息，从而提高设计新疗法帮助停止使用大麻的机会。

DESCRIPTION (provided by applicant): Cannabis is one of the most widely used psychotropic drugs and it has been linked with numerous serious adverse effects including dependence, psychiatric disorders, and cardio-respiratory disease. Detailed knowledge about the mechanisms by which this drug acts is crucial to understand its many effects, and may greatly assist the design of drugs to facilitate treatment of cannabis dependence and withdrawal. Identification of all the cannabinoid receptors is central to this problem. In addition to the two well-characterized classical cannabinoid receptors three other receptors have recently been identified. Based on its distribution and function in the brain it has also been suggested that the extracellular Ca-sensing receptor (CaSR) would be a suitable target for cannabinoids. In preliminary experiments we found that cannabinoids activate CaSR, a G-protein coupled receptor (GPCR), that is localized in the majority of nerve terminals in the brain, and decreases synaptic transmission when activated. These preliminary findings, coupled with the abundance of CaSR in the brain, may fundamentally change our understanding of the mechanism of action of cannabinoids. The objective of this proposal is to determine if CaSR is an important pathway in the action of cannabinoids and our hypothesis is that brain CaSR is activated directly by cannabinoids. We are ideally suited to perform this project because of our expertise in CaSR function in nerve terminals and expression systems. The sensitivity of CaSR to cannabinoids and the prevalence of CaSR in the brain will open up a new view of cannabinoid action, substantially changing thinking in the field. Successful completion of these specific aims will characterize the response of CaSR to cannabinoids, shedding light on the broader range of influence of CaSR. This work will define the tools necessary to dissect the relative contributions of CaSR and CB1 to cannabinoid modulation of synaptic transmission in the brain. Future proposals would combine pharmacological and genetic approaches to ascertain the impact of cannabinoids via CB1 and CaSR at central synapses. Our rationale is that the identification and characterization of a novel and prevalent cannabinoid receptor will facilitate our understanding of the behavioral actions of the commonly used drug cannabis. Moreover, distinguishing the various actions of cannabinoids may translate into the identification of a novel class of drugs that facilitate treatment of cannabis addiction and withdrawal. PUBLIC HEALTH RELEVANCE: Cannabis is a commonly used drug that is associated with drug dependence and serious psychiatric, cardiovascular and pulmonary diseases. New treatments are needed to help people stop using cannabis but this requires improved understanding of how cannabis works. We have discovered a new pathway in the brain that is activated by cannabis-like drugs. By studying this new pathway we will discover more about how cannabis works and so improve the chances of designing new treatments to help stop cannabis use.