DRUG RECEPTORS, NEUROTRANSMITTERS AND ADDICTION

这个项目的重点是阐明参与的机制 重复用药、药物的长期影响和 慢性吸毒和寻求毒品的生化机制 行为。在一系列研究中，我们用可卡因处理动物 长期的，但断断续续的时尚。管理模式是 类似于在自行注射可卡因的动物身上观察到的情况。我们 利用Lewis大鼠，因为它们表现出自我管理的倾向 可卡因与其他菌株的比较。我们发现，在10天的 戒断后，多巴胺转运体(A)显著减少 可卡因受体)结合在伏核，但不结合在 纹状体。伏隔核转运蛋白结合的减少是长期的- 持续，并在戒断后60天仍然明显。因此，有 边缘区域多巴胺转运体的长期变化 在取款期间出现，并且是永久性的。这种类型 生化现象的变化可能与药物的长期作用有关 在人类群体中。 为了阐明这种下调的机制， Transporter，我们进行了一项原位杂交研究 与乔治·乌尔博士合作。我们发现显著减少了 中脑细胞群多巴胺转运体mRNA投射到 伏隔核。在细胞组中没有发现mRNA的变化 投射到纹状体。这些数据表明，基因的变化 在停药过程中可能会出现表达，也可能会调节 多巴胺转运体可能涉及基因表达的变化。 综上所述，我们已经进行了一系列成功的研究。 慢性用药过程中多巴胺转运体的变化 和戒烟。

The focus of this project is to elucidate mechanisms involved in the repetitive use of drugs, the long-term effects of drugs and the biochemical mechanisms underlying chronic drug taking and drug seeking behavior. In a series of studies, we treated animals with cocaine in a long-term, but intermittent fashion. The pattern of administration was similar to that observed in animals self-administering cocaine. We utilized Lewis rats as they show a propensity for self administering cocaine compared to other strains. We found that, after 10 days of withdrawal, there was a significant decrease in dopamine transporter (a cocaine receptor) binding in the nucleus accumbens but not in the striatum. The decrease in transporter binding in the accumbens was long- lasting and still apparent by 60 days after withdrawal. Thus, there is a long-lasting change in dopamine transporter in limbic areas which appears during the withdrawal period and which is persistent. This type of biochemical phenomena could be related to long-term effects of drugs in human populations. In an effort to elucidate the mechanism of this down regulation of transporter, we carried out an in situ hybridization study in collaboration with Dr. George Uhl. We found a significant reduction in dopamine transporter MRNA in midbrain cell groups that project to the nucleus accumbens. Changes in MRNA were not found in cell groups projecting to the striatum. These data indicate that changes in gene expression can occur during drug withdrawal and also that regulation of the dopamine transporter can involve a change in gene expression. Taken together, we have carried out a series of successful studies in changes in the dopamine transporter during chronic drug administration and withdrawal.