TRANSITIONAL STATES IN DRUG ADDICTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类毒瘾的发展通常涉及从娱乐性药物使用到强制药物使用的转变，这会导致严重的不良后果。该项目的主要目标是描述与记录在案的猕猴可卡因使用史相关的行为和大脑功能的变化。这项受试者内的纵向设计采用了药物自我给药、药物诱导恢复、体内微透析和PET神经成像方案。受试者接受了在受限条件下自我注射可卡因的训练，随后被允许每周另外3小时、3天自我注射可卡因，以模拟一种暴饮式的吸毒模式。 在整个研究过程中，每月对可卡因作为复发模型恢复熄灭行为的有效性进行评估。在研究过程中，即使受试者在暴饮型条件下显着增加了药物摄入量，可卡因诱导的恢复也非常稳定。 第二组受试者接受了在限制使用条件(1小时/天)和延长使用条件(4小时/天)下自我注射可卡因的训练。在长期接触条件下，药物摄入量显著增加。在体内，清醒猴子的微透析显示，在有限接触条件下，基础多巴胺和代谢物减少，在延长接触条件和4周戒断条件下保持稳定。同样，可卡因和安非他明导致多巴胺增加，而多巴胺的作用减弱。 总体而言，这些结果与功能低下的多巴胺系统在戒毒后没有恢复正常是一致的。使用代谢物示踪剂FDG的PET神经成像显示，在药物初治受试者中，急性注射可卡因后，前额叶皮质得到了可靠的激活。重要的是，可卡因的这种大脑代谢效应显著增强，并招募了一些大脑区域，包括前扣带回和眶-额叶皮质，在自身服用可卡因的历史之后。这项研究得出的信息将有助于确定可卡因药物开发的相关目标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The progression of drug addiction in humans typically involves a transition from recreational to compulsive drug use that leads to serious adverse consequences. The primary objective of the project was to characterize changes in behavior and brain function associated with a well documented history of cocaine use in rhesus monkeys. This within-subject, longitudinal design employed drug self-administration, drug-induced reinstatement, in vivo microdialysis, and PET neuroimaging protocols. Subjects were trained to self-administer cocaine under limited-access conditions and subsequently were allowed to self-administer cocaine for an additional 3 hours, 3 days/week in order to model a binge-type pattern of drug use. The effectiveness of cocaine to reinstate extinguished behavior as a model of relapse was evaluated on a monthly basis throughout the study. Cocaine-induced reinstatement was remarkably stable over the course of the study even when subjects increased their drug intake significantly under the binge-type condition. A second group of subjects was trained to self-administer cocaine during limited-access conditions (1 hour/day) and extended-access conditions (4 hours/day). Drug intake increased markedly during extended-access conditions. In vivo microdialysis in conscious monkeys showed reductions in basal dopamine and metabolites following limited-access conditions that remained stable following extended-access conditions and a 4 week withdrawal condition. Similarly, cocaine- and amphetamine-induced increases in dopamine where attenuated. Collectively, the results are consistent with a hypo-functional dopamine system that did not normalize following drug abstinence. PET neuroimaging with the metabolite tracer, FDG, revealed reliable activation of prefrontal cortex following an acute injection of cocaine in drug na¿ve subjects. Importantly, this brain metabolic effect of cocaine was enhanced markedly and recruited a number of brain regions, including anterior cingulate and orbital-frontal cortex, following a history of cocaine self-administration. The information derived from the study will help identify relevant targets for cocaine medications development.