BASIC MECHANISMS OF COCAINE

可卡因的基本机制

基本信息

批准号：
6431917
负责人：
Jonathan 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, and drug abuse. Further, the research will have broader implications for the psychology of the 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; however, the stimulation of locomotor activity appears not to be related to agonist activity mediated by D3 or D4 dopamine receptors. Preliminary studies of D5 dopamine receptors suggest a minimal role of these receptors in mediating the stimulant effects of cocaine. Early results suggested that D5 dopamine receptors were involved in the regulation of sensitivity that develops to the psychomotor stimulant effects of cocaine that occur with repeated exposure. These findings appear not to be reliable. (2) The subjective behavioral effects of cocaine are mediated by both D1 and D2 dopamine receptor systems. Recent studies suggest that both D1 and D2 dopamine receptors are less involved in the subjective effects of cocaine than they are in the psychomotor stimulation produced by cocaine. Actions mediated through either system alone are not sufficient to fully reproduce the subjective effects of cocaine in rodents and primates. Current studies indicate that D4 dopamine receptors contribute minimally, if at all, to the subjective effects of cocaine. (3) Behavioral effects of cocaine related to its abuse appear to be mediated by "high-affinity" binding of cocaine to the dopamine transporter. Low affinity binding at the dopamine transporter appears to produce effects that are not related to cocaine abuse; i.e. locomotor depression rather than stimulation and discriminative stimulus effects that are different from those of cocaine. Ongoing studies are designed to independently manipulate these two populations of receptors in order to determine how those manipulations will change the response to cocaine. (4) Unique compounds based on cocaine structures have been synthesized that provide information on the nature of the interaction of cocaine with its binding site on the dopamine transporter. Recent studies have determined that analogs of cocaine with di-phenyl ether substitutions at the 2-position of the tropane ring can compete for cocaine binding sites in brain and inhibit dopamine uptake. These compounds however, do not produce cocaine-like subjective effects in animals. This is the first time that a close cocaine analog has been shown to lack a behavioral profile similar to that of cocaine. Although these compounds do not produce subjective effects like those of cocaine, they retain psychomotor stimulant effects. The separation of these two effects is not normally obtained. Therefore these compounds may be important for a better understanding and differentiation of the biological substrates that underlie these two important behavioral effects of cocaine.

这项研究的主要重点是更好地了解可卡因导致其滥用行为的行为影响的药理机制以及滥用的后果。这种更好的理解将提高对可卡因药理学和药物滥用的基础知识。此外，这项研究将对涉及强化和目标指导行为的动机过程的心理具有更广泛的影响。更好地了解可卡因和药物滥用的药理学将在我们发现新的可卡因滥用治疗方式方面取得进步，这最终将对减少药物滥用和HIV感染的传播产生积极的公共卫生影响。研究表明：（1）可卡因的精神运动刺激作用，如运动活性的增加所示，可以由D1样和D2样的多巴胺受体介导；然而，运动活性的刺激似乎与D3或D4多巴胺受体介导的激动剂活性无关。 D5多巴胺受体的初步研究表明，这些受体在介导可卡因的刺激作用中的作用最少。早期结果表明，D5多巴胺受体参与了对可卡因的精神运动刺激作用发展的敏感性，而可卡因反复暴露会发生。这些发现似乎并不可靠。（2）可卡因的主观行为效应是由D1和D2多巴胺受体系统介导的。最近的研究表明，与可卡因产生的心理刺激相比，D1和D2多巴胺受体参与可卡因的主观作用。仅通过这两个系统介导的动作就不足以完全再现可卡因在啮齿动物和灵长类动物中的主观影响。当前的研究表明，D4多巴胺受体对可卡因的主观作用造成的贡献最小。（3）可卡因与其滥用相关的行为影响似乎是由可卡因与多巴胺转运蛋白的“高亲和力”结合所介导的。多巴胺转运蛋白的低亲和力结合似乎会产生与可卡因滥用无关的作用。即运动抑郁而不是与可卡因不同的刺激和歧视性刺激作用。正在进行的研究旨在独立操纵这两个受体种群，以确定这些操纵如何改变对可卡因的反应。（4）已经合成了基于可卡因结构的独特化合物，可提供有关可卡因在多巴胺转运蛋白上的结合位点相互作用的性质的信息。最近的研究确定可卡因与二苯基醚取代的类似物在2位的2位，可以竞争脑中的可卡因结合位点并抑制多巴胺的摄取。但是，这些化合物不会在动物中产生可卡因样的主观作用。这是第一次证明可卡因类似物缺乏类似于可卡因的行为概况。尽管这些化合物不会产生像可卡因这样的主观作用，但它们保留了精神运动刺激作用。这两个效应的分离通常不会得到。因此，这些化合物对于更好地理解和分化可卡因的两种重要行为影响可能很重要。