HALLUCINOGENS PHARMACOLOGY ON 5-HT RECEPTORS SUBTYPE

这个项目的目标是了解相似性和差异性 滥用致幻药物的行为与非致幻药物的行为之间 5-羟色胺受体及其效应物上的致幻剂同类物。 了解这些分子事件是发展 合理的治疗药物，并可能提供解毒剂，这些药物 滥用以及药物药理学的一般知识 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--致幻剂是 5-HT（5-羟色胺; 5-羟色胺）激动剂，疗效低， 受体活化和脱敏的缓慢动力学。 相比之下， 化学上相关的非致幻剂是纯5-HT拮抗剂 或者是具有高效和快速作用动力学的5-HT激动剂。 我们建议研究致幻剂和结构相关的非致幻剂的作用。 两个层次的致幻剂：i）药物-受体相互作用;和ii） 与这种相互作用无关的特定细胞事件。 药物相关 将测定人5-HT 2和5-HT 1C的疗效（RE）值 受体转染到克隆细胞系中， 方法;功能和热力学结合测定。 响应 来自三个化学上不同的组的化合物的参数--麦角林， 吲哚烷基胺和苯基烷基胺-将通过测量 各种第二信使测定（肌醇磷酸的产生和 二酰基甘油，[Ca 2 +]i增加，花生四烯酸释放， 腺苷酸环化酶活性的扩增、胆碱积累和 受体的调节-腺苷酸环化酶的Gi连接的抑制）。 不同温度下药物受体复合物的热力学结合参数 亲和力状态将作为评估RE的第二种方法进行 价值观 这些方法将被药理学核心所利用， 服务于本IRPG的其他三个项目。 之间的相互作用 由不同的5-HT受体亚型（“受体”）激活的细胞途径 串扰”），如5-HT 1C对5-HT-1-β样的衰减， 药物RE值在前受体上。 此外，5-HT 1C的活化 或者5-HT 2受体与快速脱敏有关， 似乎取决于药物RE值。理念有详细 了解这些复杂的现象，我们建议研究 通过综合方法确定给定药物的药理学特征，其中 受体-药物复合物的识别和亲和力状态的改变， 第二信使产生和受体调节的动力学 （脱敏）和受体串扰的研究是在一个比较 与致幻剂和结构相关的非致幻剂的方式。 最后，由于新的5-HT受体亚型的不断发现， 可能是致幻药物滥用的重要目标，我们 我建议将同样的方法应用于一个可能的候选人，5-HT 6 受体的

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.