Structural Brain Mapping of Cocaine Action

这项拟议的工作是NIDA东查尔斯敦MGH计划项目的一部分。初步研究表明，功能磁共振成像(FMRI)测量的可卡因引起的局部脑血容量(RCBV)变化在有可卡因自我给药史的大鼠中比在药物幼稚的动物(即在食物强化行为上执行相同时间的大鼠)更持久。这项研究的目的是检验一种假设，即慢性动物的这种持续反应与慢性动物边缘结构中多巴胺释放的幅度和持续时间的增加有关。第二个目标是检验假设，即与幼稚动物相比，慢性阻塞性肺疾病患者给予多巴胺D1(SKF 81297，SKF 38393)和D2(7-OHDPAT)受体激动剂后，局部脑血流量的不同变化模式将相关。最后，这一假说将被评估，非选择性5-羟色胺(5-羟色胺)受体拮抗剂(甲硫平)和选择性5-羟色胺/1b/d部分激动剂(GR 127935)单独和与可卡因一起使用将在慢性和幼稚大鼠的局部脑血流速度产生明显的变化。这些动物将在北卡罗来纳大学医学院的行为药理学实验室进行准备和培训，然后被运送到查尔斯敦-MGH实验室的功能磁共振实验室。与其他成像技术相比，使用rCBV的fMRI测量对药物引起的变化提供了更好的时间分辨率。这项研究的结果将有助于确定随着时间的推移，长期服用可卡因如何通过多巴胺和5-羟色胺能机制改变局部脑功能的调节。

The proposed work is part of the MGH, East Charlestown Program Project to the NIDA. Preliminary research has shown that cocaine induced changes in regional cerebral blood volume (rCBV), as measured by functional magnetic resonance imaging (fMRI), are more sustained in rats with a history of cocaine self-administration than in drug naive animals (i.e. rats that have performed for an equal amount of time on a food-reinforced behavior). The purpose of the investigation proposed here is to test the hypothesis that this sustained response in chronic animals correlates with an increase in the magnitude and duration of dopamine release in limbic structures of chronic animals. A second goal is to examine the hypotheses that different patterns of change in rCBV will be associated with the administration of dopamine D1 (SKF 81297, SKF 38393) and D2 (7-OH DPAT) receptor agonists to chronic as compared to naive animals. Finally, the hypothesis will be assessed that administration of non-selective serotonin (5-HT) receptor antagonists (methiothepin) and of selective 5-HT/1b/d partial agonists (GR 127935) alone and in combination with cocaine will produce distinct alterations in rCBV in chronic and naive rats. The animals will be prepared and trained at the laboratory of Behavioral Pharmacology, BU School of Medicine and then transported to the fMRI Laboratory at the Charlestown-MGH Laboratories. Use of fMRI measures of rCBV provides better time resolution of drug induced changes than do other imaging techniques. The results of this study will help to establish how chronic cocaine self- administration alters regulation by dopaminergic and serotonergic mechanisms of regional brain function over time.