Endogenous/exogenous cannabinoids: A comparison

描述（由申请人提供）：大麻素研究取得了巨大的进步，因为发现了化学物质的特定识别位点（受体），如？-9-四氢大麻酚，大麻的主要活性成分。因此，内源性大麻素信号系统可能是大麻“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（DD）是一种评估动物“主观”经历的药物效应的强大模型，是本研究中主要的体内行为技术。大麻素受体CB1 （CB1R）激动剂和拮抗剂（逆激动剂）将在DD中使用不同剂量进行训练。这提供了不同灵敏度水平的体内试验。这项研究补充了观察性研究以及时间表控制响应，允许配体的详细表征。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。新分子由现场专家设计和合成。一个特别的重点是确定体内中性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（逆激动作用），可能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，该系统包括两个主要家族成员，以anandamide和2-花生四烯醇甘油（内源性受体配体）为代表，在正常身体功能和病理条件下作用于两种已知受体CB1和CB2。该提案的其他“治疗”靶点涉及影响内源性大麻素失活的酶的配体和不太明确的膜运输系统，因此可能避免直接受体激活。这些行为研究是由合作教师提供的神经/生化技术辅助的，以实现这些目标。通过获取身体物质（anandamide和2-AG）和大麻物质的功能信息？-9-THC，以及可能的体内中性阻断剂，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理解，而且还可能导致治疗大麻/大麻疾病的有效药物的开发。

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.