Endogenous/exogenous cannabinoids: A comparison

描述（由申请人提供）：大麻素的研究取得了巨大的进步，因为发现了特定的识别位点（受体）的化学品，如？-9-THC，大麻的主要活性成分。内源性大麻素信号系统因此可能作为大麻“高”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性障碍。药物辨别（DD）是一个强大的模型，用于评估“主观”经历的药物作用的动物，是主要的在体内的行为技术，在这个建议。大麻素受体CB 1（CB 1 R）激动剂和拮抗剂（反向激动剂）都将使用不同剂量进行DD训练。这提供了具有不同灵敏度水平的体内测定。这项研究是由观察性研究以及时间表控制的反应，允许配体的详细表征的补充。该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。新分子由现场专业人员设计和合成。一个特别的重点是确定在体内中性CB 1 R拮抗剂。目前可用的CB 1 R拮抗剂（如利莫那班）也表现出内在活性（反向激动作用），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传导系统的理解，该系统包括两个主要的家族成员，以花生四烯酸和2-花生四烯酸甘油（内源性受体配体）为代表，作用于两种已知的受体CB 1和CB 2，在正常的身体功能以及病理条件下。该提议的其他“治疗”靶点涉及影响内源性大麻素失活的酶的配体和表征不太好的膜转运系统，从而潜在地避免直接受体活化。行为研究得到了合作教师在追求这些目标时提供的神经/生物化学技术的帮助。通过获得关于身体物质（大麻素和2-AG）和大麻物质的功能的信息？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，而且还可能导致开发治疗大麻/大麻疾病的有效药物。

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.