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 casual, recreational drug use to compulsive drug use that leads to serious adverse consequences. Hence, the frequency and pattern of drug use changes as a function of drug history. This is a project in its fifth year to utilize i.v. drug self-administration protocols in rhesus monkeys to identify behavioral and neurochemical endpoints indicative of transitional states in drug addiction. The project has focused on changes in behavior and neurochemistry as subjects undergo an extensive history of cocaine self-administration. Under limited access conditions that were designed to model recreational drug use in humans, there was no consistent change in rate of extinction or in the magnitude of drug-induced reinstatement effects. However, subjects that subsequently have an opportunity to escalate drug intake during extended-access conditions did show augmented drug-induced reinstatement. Parallel in vivo microdialysis studies will document whether the behavioral changes observed are mediated through an enhanced response of dopamine. Also, PET imaging with FDG will show whether there are corresponding changes in cocaine-induced brain metabolic effects that may link behavior with neurocircuitry. Brain tissue obtained from subjects assigned to the limited-access condition has been sent to Dr. Scott Hemby at Wake Forest University to assay changes in gene expression as a function of cocaine history. The primary gene targets have emphasized components of the dopamine and glutamate systems. The results document significant changes in glutamate receptor gene expression, consistent with published reports in human cocaine overdose victims.