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-THC等化学物质的特定识别位点(受体)以来，大麻研究取得了巨大的进步。因此，内源性大麻素信号系统很可能是大麻“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(DD)是评估动物“主观”体验药物效应的有效模型，也是本提案中主要的活体行为技术。大麻素受体CB1(CB1R)激动剂和拮抗剂(反向激动剂)都将接受不同剂量的DD培训。这为体内检测提供了不同的灵敏度水平。这项研究得到了观察性研究以及时间表控制反应的补充，从而允许对配体进行详细的表征。这项提案的一个主要目标是确定新的药物，这些药物将转化为更好的药物疗法，以对抗不断升级的大麻成瘾。新的分子是由现场专业人员设计和合成的。一个特别的焦点是寻找体内中性的CB1R拮抗剂。目前可用的CB1R拮抗剂(如利莫那班)也表现出内在活性(反向兴奋)，可能会干扰患者在治疗环境中的依从性。因此，这些研究将扩大我们对内源性大麻素信号系统的理解，该系统由两个主要的家族成员组成，以内源性受体配基anandide和2-花生四烯酸甘油为代表，作用于两个已知的受体CB1和CB2，在正常身体功能和病理条件下都是如此。这项提议的其他“治疗”目标涉及影响参与内源性大麻素失活的酶的配体，以及特性较差的膜运输系统，从而潜在地避免了直接受体激活。在追求这些目标的过程中，行为研究得到了合作教师提供的神经/生化技术的帮助。通过获得体内物质(双胺和2-AG)和大麻物质？-9-THC的功能信息，以及体内可能的中性阻滞剂，这些研究不仅将增加我们对大麻滥用和依赖的行为神经生物学的了解，而且还可能导致开发有效的药物来治疗大麻/大麻疾病。

DESCRIPTION (provided by applicant): Cannabinoid research has made tremendous advances since the discovery of specific recognition sites (receptors) for chemicals like ? -9-THC, the main active ingredient in marijuana. The endocannabinoid signaling system 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 (DD) is a powerful model for assessing "subjectively" experienced drug effects in animals and is the major in vivo behavioral technique in this proposal. Both cannabinoid receptor CB1 (CB1R) agonists and antagonists (inverse agonists) will be trained in DD using different doses. This provides for in vivo assays with different sensitivity levels. This research is complemented by observational studies as well as schedule controlled responding allowing for a detailed characterization of the ligands. A major goal of this proposal is to identify new medications that will translate into better pharmacotherapies for combatting escalating marijuana addiction. New molecules are designed and synthesized by on site expertise. A particular focus is to identify in vivo neutral CB1R antagonists. Currently available CB1R antagonists (such as rimonabant) also exhibit intrinsic activity (inverse agonism) that may interfere with patient compliance in treatment settings. Thus, the studies will expand our understanding of the endocannabinoid signaling system, comprising two major family members as represented by anandamide and 2-arachidonoylglycerol (endogenous receptor ligands) acting on two known receptors, CB1 and CB2, in normal body function as well as under pathological conditions. Additional "therapeutic" targets for this proposal concern ligands affecting enzymes involved in the deactivation of the endocannabinoids and a less well characterized membrane transport system, thus potentially avoiding direct receptor activation. The behavioral studies are aided by neuro/biochemical techniques provided by collaborating faculty in pursuing these goals. By obtaining information on the functions of the body substances (anandamide and 2-AG) and the marijuana substance ?-9-THC, as well as possible in vivo neutral blocking agents, these studies will not only add to our understanding of the behavioral neurobiology of cannabis abuse and dependence, but may also lead to the development of effective medications for treating cannabis / marijuana disorders.