? 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. The proposed studies will utilize i.v. drug self-administration protocols in rhesus monkeys to identify critical behavioral endpoints indicative of transitional states in drug addiction. Efforts will focus on the importance of response-contingent drug history and drug-related environmental stimuli. Subjects will be exposed to a limited-access condition designed to incorporate features of recreational drug use in humans, followed by a binge period with increased duration of access and marked elevations in drug intake. Changes in the pattern and frequency of drug intake during the limited-access and binge conditions will be a major focus (Specific Aim 1). Reinstatement of drug-seeking behavior by cocaine priming injections and drug-paired stimuli will provide another objective behavioral measure indicative of transitional states in drug use (Specific Aim 2). Parallel studies will utilize in vivo microdialysis in awake subjects to characterize functional changes in monoamine neurochemistry associated with the behavioral changes observed (Specific Aim 3). In addition, positron emission tomography will document the pattern of drug-induced brain activation at different transitional states observed in behavioral and neurochemical studies (Specific Aim 4). Brain tissue obtained at different transitional states will be assayed for gene expression profiles and protein products, providing relevant molecular markers to complement in vivo functional measures in a nonhuman primate model of drug use (Specific Aim 5). These integrated efforts, including behavioral and mechanistic approaches, will provide a comprehensive analysis to elucidate transitional states in cocaine addiction. ? ?
