BASIC MECHANISMS OF COCAINE'S BEHAVIORAL EFFECTS

可卡因行为影响的基本机制

• 批准号: 3775013
• 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/3775013
• 关键词: Primates; chemical synthesis; cocaine; crack cocaine; dopamine agonists; dopamine antagonists; dopamine receptor; drug abuse; drug screening /evaluation; drug tolerance; laboratory rat; psychopharmacology; receptor binding; reinforcer; transport proteins

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. Studies have indicated that: (1) the D1 dopamine receptor appears to be more involved than originally concluded in the subjective behavioral effects of cocaine in the monkey than was indicated in the rat. This was established by studying several D1 dopamine receptor agonists. In addition, there is evidence that non dopaminergic effects may be important components of the pharmacological profile cocaine, and these will be studied further. (2) The D1 dopamine-receptor agonist, SKF 38393, blocked the reinforcing effects of cocaine. This effect occurred at doses that had minimal effects on other behaviors. These results suggest that D1 agonists may be useful treatments against cocaine abuse. (3) Studies have continued on the modulation of the effects of cocaine by various types of agents. In particular, studies have examined the effects of sigma receptor ligands and antagonists of excitatory amino acids. (4) The mechanism of the modulation of the effects of cocaine by sigma receptor ligands has been assessed. It appears that some sigma ligands bind to the dopamine transporter. However, these drugs do not produce behavioral effects like those of cocaine. This may be the mechanism for the antagonism of the psychomotor stimulant effects of cocaine by sigma receptor ligands. (5) Tolerance and sensitization can develop to the behavioral effects of cocaine. The mechanisms for these two effects of repeated cocaine dosing are being studied. (6) The synthetic chemistry component of the laboratory has synthesized pyrolysis products of cocaine that have been identified in crack-cocaine users. These compounds do not have cocaine-like effects but do have some structural similarities to known cholinergic toxins. The pharmacology of these compounds is being characterized. (7) Dopamine uptake inhibitors have been synthesized that do not have behavioral effects like those of cocaine. The pharmacology of these drugs is being studied to provide structure-activity relations that will provide basic information on the functioning of 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 可卡因导致滥用及其虐待的后果。 研究表明：（1）D1多巴胺受体似乎是 比主观行为最初得出的要多 可卡因在猴子中的影响比大鼠中所示。 这是 通过研究几种D1多巴胺受体激动剂来建立。 在 此外，有证据表明非多巴胺能作用可能是 药理学特征可卡因的重要组成部分，这些成分 将进一步研究。 （2）D1多巴胺受体激动剂，SKF 38393， 阻止了可卡因的增强作用。 这种效果发生在 对其他行为影响最小的剂量。 这些结果表明 D1激动剂可能是针对可卡因滥用的有用治疗方法。 （3） 研究继续研究可卡因对可卡因的影响 各种类型的代理。 特别是，研究检查了 Sigma受体配体和兴奋性氨基的拮抗剂的影响 酸。 （4）调节可卡因作用的机制 Sigma受体配体已评估。 看来一些西格玛 配体与多巴胺转运蛋白结合。 但是，这些药物没有 产生类似可卡因的行为影响。 这可能是 拮抗精神运动刺激作用的机制 Sigma受体配体可卡因。 （5）公差和敏化可以 发展为可卡因的行为影响。 这些机制 正在研究重复可卡因剂量的两个影响。 （6） 实验室的合成化学成分已合成热解 可卡因的产品已在裂纹可卡因用户中鉴定出来。 这些化合物没有类似可卡因的效果，但确实有一些 与已知胆碱能毒素的结构相似性。 药理学 这些化合物的特征是。 （7）多巴胺摄取 抑制剂已被合成，没有行为影响 可卡因的人。 这些药物的药理学正在研究 提供结构活动关系，以提供基本信息 关于多巴胺转运蛋白的功能。