DRUG RECEPTORS, NEUROTRANSMITTERS AND ADDICTION

该项目的重点是成瘾的某些具体组成部分， 即重复使用药物，药物的长期影响， 成瘾行为背后的生化机制 换句 项目，我们已经开发了一种小鼠模型，用于体内标记 多巴胺转运蛋白结合配体。 在这其中的某些组成部分， 项目，我们利用这个模型来检查体内结合效力的 各种新的可卡因类似物以及化合物可以 进入大脑并占据可卡因受体-多巴胺转运蛋白。 在 在体内受体结合研究中，我们发现几种可卡因类似物 在体外表现出高效力的菌株在体内也表现出高效力。 此外，有证据表明，最大的运动效果，这些 类似物在导致接近最大占据率的剂量下发生， 转运站 此外，这些化合物在大鼠中取代了可卡因 训练他们区分可卡因和盐水 这些化合物来自六个 比可卡因强13倍 适当的回应。 因此，这些数据支持这样的观点， 多巴胺摄取抑制是行为效应的一个组成部分， 可卡因及其类似物。 人们常说，药物进入人体后， 大脑更快地上瘾。 通过利用体内受体 结合模型，它是可能的，以量化如何迅速进入药物 大脑和占领受体通过观察大鼠的位移 各种药物在体内的配体结合。 通过使用放射性标记的 WIN-35，428在体内，有可能表明可卡因占据了其 GBR-12909对受体的抑制作用比GBR-12909快，而马吲哚最慢。 这些研究是合理的第一步，能够量化 快速药物进入大脑，并评估这一因素对 这些化合物的成瘾倾向。

The focus of this project is on certain specific components of addiction, namely the repetitive use of drugs, the long-term effects of drugs, and the biochemical mechanisms underlying addictive behavior. In other projects, we have developed a mouse model for the in vivo labeling of dopamine transporters by binding ligands. In some components of this project, we utilize this model to examine the in vivo binding potency of various novel cocaine analogs as well as the rate at which compounds can enter the brain and occupy cocaine receptors-dopamine transporters. In in vivo receptor binding studies, we found that several cocaine analogs that displayed high potency in vitro also displayed high potency in vivo. Moreover, evidence suggests that maximal locomotor effects of these analogs occur with doses resulting in near maximal occupancy of transporter sites. Also, these compounds substituted for cocaine in rats trained to discriminate cocaine from saline. The compounds were from six to thirteen times more potent than cocaine in producing cocaine appropriate responding. Thus, these data support the notion that dopamine uptake inhibition is a component of behavioral effects of cocaine and its analogs. It is commonly said that drugs that enter the brain more rapidly are more addicting. By utilizing in vivo receptor binding models, it is possible to quantify how rapidly drugs enter the brain and occupy receptors by looking at the rat of displacement of ligand binding in vivo by various drugs. By using radiolabeled WIN-35,428 in vivo, it was possible to show that cocaine occupies its receptors more rapidly than GBR-12909 while mazindol was the slowest. These studies are a reasonable first step to being able to quantify how rapidly drugs enter the brain and to assess the role of this factor on the addiction liability of these compounds.