TRANSITIONAL STATES IN DRUG ADDICTION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人类药物成瘾的进展通常涉及从娱乐性药物使用到导致严重不良后果的强迫性药物使用的转变。该项目的主要目的是描述与恒河猴可卡因使用史相关的行为和脑功能变化。 这种受试者内的纵向设计采用了药物自我给药、药物诱导的恢复、体内微透析和PET神经成像方案。 受试者接受了在限制进入条件下自我给药可卡因的培训，随后被允许额外3小时、3天/周自我给药可卡因，以模拟狂欢型药物使用模式。 在整个研究中，每月评估可卡因恢复作为复发模型的熄灭行为的有效性。可卡因诱导的恢复在研究过程中非常稳定，即使受试者在暴食型条件下显著增加药物摄入量。 第二组受试者接受培训，在有限访问条件（1小时/天）和扩展访问条件（4小时/天）期间自我管理可卡因。药物摄入量显着增加，在扩大访问条件。在清醒的猴子体内微透析显示，基础多巴胺和代谢物减少后，有限的访问条件下，保持稳定后，扩展访问条件和4周的戒断条件。同样，可卡因和安非他明诱导的多巴胺增加减弱。 总的来说，这些结果与在药物戒断后没有正常化的功能低下的多巴胺系统一致。 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，前额叶皮层的激活是可靠的。 重要的是，可卡因的这种脑代谢作用显著增强，并招募了许多脑区，包括前扣带回和眶额皮质，可卡因自我管理的历史。从这项研究中获得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.