BEHAVIORAL PHARMACOLOGY OF DOPAMINE SYSTEMS

多巴胺系统的行为药理学

• 批准号: 3775015
• 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/3775015
• 关键词: Primates; behavioral medicine; dopamine agonists; dopamine antagonists; dopamine receptor; drug abuse; laboratory rat; psychopharmacology; stereochemistry

Studies have been conducted to better document the behavioral pharmacology of drugs acting on dopaminergic systems. These studies have examined specific D1, D2, and D3 dopamine receptor agonists and antagonists. The overall goal of these studies is to better characterize the behavioral pharmacology of drugs acting on these systems and the mechanisms responsible for those behavioral effects. These studies indicate that: (1) some of the D2 agonists can stimulate behavior in a manner similar to cocaine, suggesting that the stimulant effects of cocaine are due to actions mediated through D2 receptors. However, some of the D2 agonists do not have effects that are equivalent to cocaine. An in vitro assay of intrinsic efficacy is being established in order to determine if the differences among these drugs are due to differences in intrinsic efficacy. There currently are no assays available to provide that information. (2) the D1 agonist, SKF 38393, is not well antagonized by D1 antagonists, whereas other D1 agonists are. These results indicate that much of the behavioral effects often attributed to D1 agonist activity of SKF 38393 are likely a result of activation of other mechanisms. Several biochemical studies are being initiated to better understand the actions of D1 agonsits. (3) D2 agonists produce a unique scratching behavior in primates. This effect of these agonists appears to be pharmacologically specific (drugs acting by other mechanisms generally do not produce this effect). Recently, we observed that the D3 agonist, 7-OH-DPAT, also produces this effect, and experiments are being conducted to determine whether the effect of 7-OH-DPAT is being mediated by D2 or D3 receptors. This effect could serve as a good in vivo assay of D2 receptor activity and will be useful in documenting the D2 agonist activity of novel compounds. In addition, it may be used to characterize the D2 agonist sensitivity of primates with various exposures to cocaine, or those that may be acutely sensitive to the effects of drugs of abuse. (4) Biochemical studies have indicated that the D1 receptor in rodents and primates may be significantly different. These results suggest that there has been a phylogeny of the D1 receptor, and that the effects of drugs acting at this receptor in man may not be predictable from studies in rodents.

进行了研究以更好地记录行为 作用于多巴胺能系统的药物。 这些研究有 检查了特定的D1，D2和D3多巴胺受体激动剂和 对手。 这些研究的总体目标是更好地表征 作用于这些系统的药物的行为药理学和 负责这些行为影响的机制。 这些研究 表明：（1）一些D2激动剂可以刺激A中的行为 与可卡因相似的方式表明 可卡因是由于通过D2受体介导的作用。但是，有些 D2激动剂中的作用不等于可卡因。 为了建立一种内在功效的体外测定 确定这些药物之间的差异是否是由于差异 内在功效。 目前没有可用的测定 这些信息。 （2）D1激动剂，SKF 38393，无法很好地拮抗 由D1拮抗剂，而其他D1激动剂是。这些结果表明 通常归因于D1激动剂的行为效应 SKF 38393的活性可能是由于其他激活的结果 机制。 正在启动几项生化研究以更好 了解D1刺激的动作。 （3）D2激动剂产生独特的 灵长类动物中的刮擦行为。 这些激动剂的这种影响似乎 是特定于药理的（通过其他机制作用的药物 通常不会产生这种效果）。 最近，我们观察到 D3激动剂（7-OH-DPAT）也会产生此效果，实验是 进行以确定7-OH-DPAT的影响是否正在 由D2或D3受体介导。 这种效果可能是一种好处 D2受体活性的体内测定，将有用 新型化合物的D2激动剂活性。 另外，它可以用来 表征具有各种灵长类动物的D2激动剂灵敏度 暴露于可卡因，或可能对可卡因敏感的 滥用药物的影响。 （4）生化研究表明 啮齿动物和灵长类动物中的D1受体可能显着差异。 这些结果表明，D1受体的系统发育 而且，在人类中作用于该受体的药物的作用可能不是 可以从啮齿动物的研究中预测。