TRANSITIONAL STATES IN DRUG ADDICTION

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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.