DRUG RECEPTORS, NEUROTRANSMITTERS AND ADDICTION

该项目的一个重点是阐明参与的机制， 长期、重复使用药物所导致的变化。 在一个 在这项研究中，我们使用了刘易斯大鼠，因为它们表现出更大的倾向， 与其他菌株相比，自我施用可卡因， 可卡因在一个长期的，但间歇性的方式，并发现有 停药后10天多巴胺转运蛋白减少。 的 早期变化不明显，停药期 需要产生变化，因为连续给药 同样的时间并没有导致这种减少。 减少 在边缘系统的一个区域--丘脑核中发现了一种转运蛋白 与成瘾有关，而不是在纹状体，一个与成瘾有关的区域， 具有运动功能。 转运蛋白的减少持续时间较长， 停药后60天仍明显。 这些长期变化是 非常有趣，并表明在大脑中的长期变化， 从可卡因中戒断的人类受试者。 为了了解这种减少的机制，我们测试了是否 或不存在转运蛋白的信使RNA减少， 发现转运蛋白下调的时间。 因为 只有少数多巴胺能神经元细胞群投射到 作为一个科学家，有必要进行这项研究， 显微镜原位杂交研究，因为它提供了 必要的解剖分辨率，以确定不同的细胞群， 含有多巴胺能的神经元。 原位杂交研究 揭示了不同水平的信使RNA， 不同细胞群中的多巴胺转运蛋白。 在药物治疗和 撤回的动物，发现有显着减少， 在束间核和尾侧核的mRNA结合水平 线状核，但不存在于中脑的其他细胞群中。 这些 两个细胞群显示出减少的投射到细胞。 因为 细胞之间的解剖学对应显示mRNA的减少 和神经终端领域显示减少转运结合，我们 假设两者之间存在直接联系，并建议 转运蛋白的调节是由于mRNA表达的减少。 这些结果表明，从长期药物给药中撤出， 可能会导致一系列复杂但持久的变化 脑生化参数 该项目目前的方向是 目的是鉴定另外的蛋白质或酶或转运蛋白， 受到长期用药的影响。

One focus of this project is to elucidate mechanisms involved in and changes consequent to the long-term, repetitive use of drugs. In one study, we used Lewis rats because they show a greater propensity for self-administering cocaine compared to other strains, treated them with cocaine in a long-term but intermittent fashion and found that there was a decrease in the dopamine transporter at 10 days after withdrawal. The change was not evident at earlier times and a withdrawal period was necessary to generate the change as continuous drug administration for the same amount of time did not result in such a decrease. The decrease in transporter was found in the nucleus accumbens, a limbic area associated with addiction, and not in the striatum, an area associated with motoric function. The decrease in transporter was long lasting and still apparent at 60 days after withdrawal. These long term changes are quite intriguing and suggest very long term changes in the brains of human subjects who are withdrawn from cocaine. In order to understand the mechanism of this decrease, we tested whether or not there is a decrease in the messenger RNA for the transporter at the time when the transporter was found to be down-regulated. Because only a small number of the dopaminergic neuronal cell groups project to the accumbens, it was necessary to carry out this study as a light microscopic in situ hybridization investigation as it provided the necessary anatomic resolution to identify the various cell groups of dopaminergic-containing neurons. The in situ hybridization studies revealed that there were different levels of messenger RNA for the dopamine transporter in the different cell groups. In drug-treated and withdrawn animals, it was found that there was a significant reduction in mRNA binding levels in the interfascicular nucleus and in the caudal linear nucleus, but not in the other cell groups of the midbrain. These two cell groups that showed a decrease project to the accumbens. Because of the anatomical correspondence between cells showing a decrease in mRNA and nerve terminal fields showing a decrease in transporter binding, we assume a direct connection between the two and suggest that the down regulation in transporter is due to a decrease in expression of the mRNA. These results indicate that withdrawal from chronic drug administration can result in a series of complicated but long-lasting changes in biochemical parameters in brain. Current directions of this project are aimed at identifying additional proteins or enzymes or transporters that are affected by chronic drug administration.