BASIC MECHANISMS OF COCAINE'S BEHAVIORAL EFFECTS

可卡因行为影响的基本机制

基本信息

批准号：
2571599
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
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

The primary focus of this research is to develop a better understanding of the pharmacological mechanisms underlying the behavioral effects of cocaine that lead to its abuse, and the consequences of that abuse. This better understanding will advance basic knowledge of the pharmacology of cocaine, drug abuse, and have broad implications for the psychology of motivational processes involved in reinforcement and goal-directed behavior. A better understanding of the pharmacology of cocaine and drug abuse will lead to advances in our discovery of new treatment modalities for cocaine abuse which will ultimately have a positive public health impact in curtailing drug abuse and the transmission of HIV infection. Studies have indicated that: (1) The psychomotor stimulant effects of cocaine, as indicated by increases in locomotor activity, may be mediated by D1-like and D2-like dopamine receptors. (2) The subjective behavioral effects of cocaine are mediated by both D1, D2, and D3 dopamine receptor systems, although actions through either system alone are not sufficient to fully reproduce the subjective effects of cocaine in rodents and primates.(3) Behavioral effects of cocaine related to its abuse appear to be mediated by Ahigh-affinity binding of cocaine to the dopamine transporter.(4) Chronic exposure to cocaine produces an up-regulation of the mu-opioid system without changes in delta-mediated function. In addition, there are increases and decreases in prodynorphin gene expression, with increases in caudate-putamen and decreases in hypothalamus. (5) Unique compounds based on cocaine or benztropine structures have been synthesized that provide information on the nature of the interaction of cocaine with its binding site on the dopamine transporter. The results of these studies confirm that steric factors at this part of the molecule are not as influential in affecting affinity as are electrostatic factors and that an electron-rich moiety favors high affinity binding. A series of benztropine analogs has been synthesized with compounds that lack cocaine-like behavioral effects despite in vitro binding to the dopamine transporter and inhibition of dopamine uptake. Structure-activity studies indicate that the binding of these compounds to the dopamine transporter is different from that for cocaine. Reasons for the lack of cocaine-like behavioral effects have been investigated. The antimuscarinic effects and a lack of CNS penetration have been excluded as explanations for the the differences between these drugs and cocaine. Because these compounds bind to the dopamine transporter but do not have cocaine-like behavioral effects, they may serve as tools for a better understanding of how the effects of cocaine are mediated by actions at the dopamine transporter.

这项研究的主要重点是建立更好的理解属于行为影响的药理机制可卡因会导致滥用，以及这种虐待的后果。这更好的理解将促进对药理学的基本知识可卡因，毒品滥用，并对涉及加强和目标指导的励志过程行为。更好地了解可卡因和药物的药理学滥用将导致我们发现新的治疗方式的进步对于可卡因滥用，最终将有积极的公共卫生削减药物滥用和艾滋病毒感染的传播的影响。研究表明：（1）精神运动的刺激作用可卡因，如运动活性的增加所示，可以介导由D1样和D2样多巴胺受体。（2）主观行为可卡因的作用是由D1，D2和D3多巴胺受体介导的系统，尽管仅通过两种系统的操作就不够充分再现可卡因在啮齿动物和灵长类动物。（3）可卡因与滥用相关的行为影响可卡因与多巴胺的亲密关系结合来介导转运蛋白。（4）长期暴露于可卡因会产生上调的上调 Mu-Apioid系统没有DELTA介导的功能变化。在此外，prodynorphin基因的增加和减少表达，随着尾状药物的增加，并减少下丘脑。（5）基于可卡因或苯甲衣的独特化合物已经合成了提供有关性质信息的结构可卡因与多巴胺上的结合位点的相互作用转运蛋白。这些研究的结果证实了空间因素该分子的这一部分对影响亲和力没有影响以及静电因子，并且富含电子的部分有利于高的部分亲和力结合。已经合成了一系列苯二甲胺类似物尽管体外与多巴胺转运蛋白的结合并抑制多巴胺摄取。结构活性研究表明这些化合物的结合多巴胺转运蛋白与可卡因不同。原因由于缺乏可卡因样的行为效应。抗毒式效应和中枢神经系统渗透的效果已经排除了这些药物和这些药物之间差异的解释可卡因。因为这些化合物与多巴胺转运蛋白结合，但没有类似可卡因的行为效应，它们可能是更好地了解可卡因的影响是如何介导的多巴胺转运蛋白的作用。