BASIC MECHANISMS OF COCAINE'S BEHAVIORAL EFFECTS

可卡因行为影响的基本机制

• 批准号: 3752845
• 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/3752845
• 关键词: behavioral habituation /sensitization; cocaine; crack cocaine; dopamine agonists; dopamine antagonists; dopamine receptor; drug abuse; drug addiction antagonist; drug metabolism; drug screening /evaluation; drug tolerance; membrane transport proteins; neurotoxins; neurotransmitter transport; psychopharmacology; receptor binding; reinforcer

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 psychomotor stimulant effects of cocaine, as indicated by increases in locomotor activity, are mediated by both D1 and D2 dopamine receptors. For increase in learned operant behavior produced by cocaine, however, D2 receptors have a greater involvement than do D1 receptors. The respective roles of other dopamine receptors are currently under investigation. (2) There are differences among dopamine uptake inhibitors in the relationships of their behavioral effects and their affinity for the dopamine transporter. For drugs that have a structural similarity to cocaine there is a direct relation between affinity for the transporter and in vivo potency. In contrast, for structurally dissimilar compounds their is no simple relationship. These data indicate that cocaine and its congeners bind to the dopamine transporter in a manner that is distinct from that of other dopamine uptake inhibitors. (3) The subjective behavioral effects of cocaine are mediated by both D1 and D2 dopamine receptor systems, although actions through either system alone are not sufficient to fully reproduce the subjective effects of cocaine. (4) The subjective behavioral effects of low doses of cocaine are mediated by both D1 and D2 dopamine receptor systems, although actions through the D1 dopamine system appear to predominate. In addition, the subjective effects of low doses of cocaine have a significant noradrenergic component that is not evident in the effects of higher doses of cocaine. (5) Anhydroecgonine methyl ester (AEME) is a major pyrolysis product of cocaine and has been detected in high concentration in the urine of subjects who have smoked "crack." In addition, AEME has a structural resemblance to anatoxin-A, a known cholinergic toxin. The contribution of AEME to the unique pharmacological actions of "crack" was investigated. These studies found that AEME probably does not contribute in a significant way to the stimulant or subjective effects of "crack" or its toxicity. (6) Tolerance to the behavioral effects of cocaine is not accompanied by changes in the function of dopamine D1 receptors. Further studies are being conducted to assess the effects of cocaine treatment on functional aspects of other dopamine receptor subtypes. (7) Unique compounds have been synthesized that have high affinity for the dopamine transporter and inhibit dopamine uptake. However, these drugs do not have behavioral effects that are similar to those of cocaine. Initial structure-activity studies indicate that the binding of these compounds to the dopamine transporter is different from that for cocaine. Because these compounds bind to the dopamine transporter but do not have cocaine-like behavioral effects, they may serve as cocaine antagonists, which is currently under investigation.

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）精神运动的刺激作用 可卡因，如运动活性的增加所示，可卡因被介导 通过D1和D2多巴胺受体。 为了增加学习的操作员 但是，可卡因产生的行为，D2受体具有更大的 与D1受体相比，参与。 其他多巴胺的各自作用 当前正在研究受体。 （2）有差异 在其行为关系中的多巴胺摄取抑制剂中 影响及其对多巴胺转运蛋白的亲和力。 对于那个药物 与可卡因具有结构性相似性，有直接关系 在转运蛋白和体内效力之间的亲和力之间。 相比之下， 对于结构上不同的化合物，它们不是简单的关系。 这些数据表明可卡因及其同源物与多巴胺结合 转运蛋白的方式与其他多巴胺不同 摄取抑制剂。 （3）可卡因的主观行为影响是 由D1和D2多巴胺受体系统介导的，尽管作用 仅通过这两个系统就不足以完全复制 可卡因的主观影响。 （4） 低剂量可卡因是由D1和D2多巴胺受体介导的 系统，尽管通过D1多巴胺系统的动作似乎 占主导。 另外，低剂量可卡因的主观影响 具有重要的去甲肾上腺素能成分，在 较高剂量可卡因的影响。 （5）甲基甲酯甲酯 （Aeme）是可卡因的主要热解产物，已在 吸烟“裂缝”的受试者的尿液中高浓度。 在 此外，AEME与Anatoxin-A具有结构相似，已知 胆碱能毒素。 Aeme对独特的贡献 研究了“裂缝”的药理作用。 这些研究发现 Aeme可能不会以重要的方式贡献 “裂纹”或其毒性的刺激性或主观作用。 （6） 对可卡因行为影响的耐受性不伴随 多巴胺D1受体功能的变化。 进一步的研究是 进行评估可卡因治疗对功能的影响 其他多巴胺受体亚型的方面。 （7）独特化合物具有 合成了对多巴胺转运蛋白和 抑制多巴胺摄取。 但是，这些药物没有行为 与可卡因相似的影响。 初始结构活性 研究表明这些化合物与多巴胺的结合 转运蛋白与可卡因不同。 因为这些化合物 与多巴胺转运蛋白结合，但没有可卡因样行为 效果，它们可能是可卡因拮抗剂，目前正在 调查。