HALLUCINOGENS PHARMACOLOGY ON 5-HT RECEPTORS SUBTYPE

这个项目的目标是了解相似和不同之处 在滥用致幻药物和非致幻药物的行为之间 5-羟色胺受体及其效应器上的致幻剂同系物。 对这些分子事件的理解是发展所必需的 合理的治疗药物，并可能为这些药物提供解毒剂 滥用的知识，以及对 改变行为的药物。这个项目的基本假设是-- 这是四个IRPG提案的一个组成部分--迷幻剂是 5-羟色胺(5-羟色胺；5-羟色胺)激动剂，低效和 受体激活和脱敏的缓慢动力学。相反， 化学上相关的非致幻剂要么是纯5-羟色胺拮抗剂 或为5-羟色胺激动剂，有效率高，起效快。 我们建议研究致幻剂的作用和结构上相关的非 两个层次的致幻剂：一)药物-受体相互作用；和二) 这种相互作用远端的特定细胞事件。毒品亲属 将测定人体5-HT2和5-HT1C的功效(RE)值 两种互补基因导入克隆细胞系的受体 方法；功能和热力学结合分析。响应 来自三个不同化学基团的化合物的参数-麦角碱， 吲哚-烷基胺和苯基烷胺-将通过测量确定 各种第二信使分析(生产肌醇磷酸盐和 二酰甘油，升高[钙]i，花生四烯酸释放， 腺酰环化酶活性、胆碱蓄积和 受体的调节-GI连锁的腺酰环化酶抑制)。 药物受体复合体在不同温度下的热力学结合参数 亲和力状态将作为评估RE的第二种方法 价值观。这些方法将被药理核心利用， 服务于此IRPG的其他三个项目。之间的相互作用 不同5-羟色胺受体亚型(“受体”)激活的细胞通路 串扰“)，例如5-HT1C对5-羟色胺-1-β的衰减，改变 药物在前者受体上的RE值。此外，5-HT1C的激活 或者5-HT2受体与快速脱敏有关， 似乎依赖于药物的RE值。为了获得一个详细的 理解这些错综复杂的现象，我们建议研究 一种特定药物的综合方法的药理学概况，其中 受体-药物复合体亲和力状态的识别和变化， 第二信使生成和受体调节的动力学 (脱敏)和受体串扰是一种比较研究 使用迷幻剂和结构上相关的非迷幻剂的方式。 最后，由于不断发现新的5-羟色胺受体亚型 这可能是迷幻药物滥用的重要目标，我们 建议将同样的方法应用于可能的候选人-5-HT6 受体。

The goal of this project is to understand similarities and differences between actions of hallucinogenic drugs of abuse and their non hallucinogen congeners on serotonin receptors and their effectors. Understanding of these molecular events is required for the development of rational therapeutic agents and may provide antidotes to these drug of abuse as well as for the general knowledge of the pharmacology of behavior-altering drugs. The underlying hypothesis of this project-- which is one component of a four IRPG proposal--is that hallucinogens are 5-HT (5-hydroxytryptamine; serotonin) agonists, with low efficacy and slow kinetics of receptor activation and desensitization. By contrast, the chemically related non-hallucinogens are either pure 5-HT antagonists or are 5-HT agonists with high efficacy and a fast kinetic of action. We propose to study actions of hallucinogens and structurally related non hallucinogens at two levels: i) drug-receptor interaction; and ii) specific cellular events distal to this interaction. Drug relative efficacy (RE) values will be determined on human 5-HT2 and 5-HT1C receptors transfected into clonal cell lines by two complementary approaches; functional and thermodynamic binding assays. Response parameters to compounds from three chemically distinct groups--ergolines, indolealkylamines and phenylalkylamines--will be determined by measuring various second messenger assay (production of inositol phosphates and diacylglycerol, increased [Ca2+]i, arachidonic acid release, amplification of adenylyl cyclase activity, choline accumulation and modulation of receptor-Gi linked inhibition of adenylyl cyclase). Thermodynamic binding parameters of drug receptor complex at different affinity states will be carried out as the second approach to assess RE values. These methods will be utilized by the pharmacological core that serves the other three projects in this IRPG. Interactions between cellular pathways activated by distinct 5-HT receptor subtypes ("receptor cross talk"), such as the attenuation 5-HT-1-beta-like by 5-HT1C, alters drug RE values on the former receptor. Also, activation of the 5-HT1C or the 5-HT2 receptor is associated with a rapid desensitization that appears to be dependent on drug RE values. To gain a detailed understanding of these intricate phenomena, we propose to study the pharmacological profile of a given drug by an integrated approach, where recognition and changes of affinity states of receptor-drug complex, kinetics of second messenger generation and of receptor modulation (desensitization) and receptor cross-talk are studies in a comparative manner with hallucinogens and structurally related non hallucinogens. Finally, due to the continuous discovery of novel 5-HT receptor subtype that may be important targets for hallucinogenic drugs of abuse, we propose to apply the same approach to a likely candidate, the 5-HT6 receptor.