BEHAVIORAL PHARMACOLOGY OF DOPAMINE SYSTEMS

多巴胺系统的行为药理学

• 批准号: 3752847
• 负责人: J L KATZ
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752847
• 关键词: central nervous system stimulants; clone cells; cocaine; dopamine agonists; dopamine antagonists; dopamine receptor; drug abuse; overdose; poisoning; psychopharmacology

The dopaminergic system is clearly implicated as important in mediating the effects of many drugs of abuse, as well as Parkinsons disease, and schizophrenia. Our studies have as their goals the determination of the functional significance of the dopamine system in normal functioning, as well as how it acts to subserve drug abuse. One specific objective is to better characterize the pharmacology of the various subtypes of CNS dopamine receptors. Included in this goal is the identification of drugs that act selectively and with high efficacy. In many cases the pharmacological tools for the study of these receptor subtypes in vivo and in vitro are limited. As a result, one further goal is the discovery of new synthetic entities that will allow analysis of the pharmacology of these dopamine receptor subtypes. These studies indicate that: (1) While it is possible to differentiate D1 dopamine agonists in vitro on the basis of their intrinsic efficacy, differences in the efficacy of the drugs have not been correlated with any other observed pharmacological effect of these drugs. (2) Studies of the behavioral effects of the D1 dopamine agonist, SKF 38393, have indicated few of its behavioral effects are mediated by actions at D1 dopamine receptors. This finding is important because SKF 38393 is often used as a prototype D1 agonist. (3) Dopamine D1, but not dopamine D2, receptors are involved in the lethal effects of acutely administered cocaine. We are preparing D1 antagonists that do not penetrate the blood brain barrier. These drugs may serve as antidotes to acute cocaine overdose and will also serve as tools for the investigation of the function of the peripheral D1 dopamine system. (4) Dopamine D2 agonists can stimulate this behavior in a manner similar to the manner in which cocaine or amphetamine stimulate behavior, in contrast, D1 agonists do not. These differences suggest an involvement of D2 dopamine receptors in the stimulant behavioral effects, and a lack of involvement of D1 dopamine receptors. (5) The pharmacology of dopamine D2 agonists is being characterized in a cell line that expresses a D2 receptor that is functionally similar to brain dopamine D2 receptors. Because these D2 receptors are expressed in the absence of other dopamine receptor subtypes, this cell line is a model system for studying the function and regulation of the D2 receptor. The findings from these studies suggest that the dopamine D2 receptor regulates cyclase inhibition predominantly via the Gi1 and/or Gi2 subunits of G-alpha. Using this system the intrinsic efficacies of dopamine D2 agonists have been characterized. These studies also indicated an intriguing link between the Gi3 subunit and the Gi1 or Gi2 subunits. (6) The pharmacology of the putative D3 receptor agonist, 7-OH-DPAT, is being characterized. These behavioral and in vitro studies have indicated that 7-OH-DPAT is a weak partial agonist at D2 receptors, and several of its effects may be mediated by that activity rather than D3 agonist activity.

多巴胺能系统显然暗示着介导 许多虐待药物以及帕金森病的影响以及 精神分裂症。 我们的研究是他们的目标的确定 多巴胺系统在正常功能中的功能意义，AS 以及它如何采取滥用药物的行为。 一个具体目标是 更好地表征CNS各种亚型的药理学 多巴胺受体。 该目标包括识别药物 该行动有选择地，具有高效能。 在许多情况下 研究这些受体亚型体内的药理工具 体外受到限制。 结果，另一个目标是发现 新的合成实体，可以分析药理学 这些多巴胺受体亚型。 这些研究表明：（1） 虽然可以在体外区分D1多巴胺激动剂 它们内在疗效的基础，效力的差异 药物尚未与任何其他观察到的药理相关 这些药物的作用。 （2）研究D1的行为效应 多巴胺激动剂，SKF 38393，表明其行为效应很少 由D1多巴胺受体的作用介导。 这个发现是 重要的是，因为SKF 38393通常用作原型D1激动剂。 （3） 多巴胺D1，而不是多巴胺D2，受体参与致命 急性施用可卡因的作用。 我们正在准备D1拮抗剂 不会穿透血脑屏障。 这些药物可能是 急性可卡因过量的解毒剂，也将作为工具 研究周围D1多巴胺系统功能。 （4） 多巴胺D2激动剂可以以类似的方式刺激这种行为 可卡因或苯丙胺刺激行为的方式， 对比，D1激动剂没有。 这些差异表明参与 在刺激性行为效应中的D2多巴胺受体的 D1多巴胺受体的参与。 （5） 多巴胺D2激动剂正在以表达的细胞系中进行表征 与脑多巴胺D2在功能上相似的D2受体 受体。 因为这些D2受体在没有 其他多巴胺受体亚型，该细胞系是一个模型系统 研究D2受体的功能和调节。 发现 从这些研究中，多巴胺D2受体调节 循环酶抑制主要通过GI1和/或GI2亚基 G-alpha。 使用该系统多巴胺D2的固有功效 激动剂的特征是。 这些研究还表明 GI3亚基与GI1或GI2亚基之间的有趣联系。 （6） 假定的D3受体激动剂7-OH-DPAT的药理学正在 特征。 这些行为和体外研究表明 7-OH-DPAT是D2受体的弱部分激动剂，其中几种 效应可能是由该活性而不是D3激动剂活性介导的。