? To date, there is no effective medication for treating cocaine addiction. A better understanding of the manner by which cocaine exerts its effects on the brain will focus medication development efforts. Although cocaine blocks the reuptake of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine, the reinforcing effects of cocaine have been primarily attributed to its effects at the dopamine transporter (DAT). However, not all DAT inhibitors are equally reinforcing. Examining the pharmacokinetics, more specifically, the onset and duration of action, of cocaine and related compounds is important in determining which of these properties are involved in the reinforcing effects of these compounds. In the present research proposal, the reinforcing effectiveness of several monoamine transporter inhibitors (DAT-selective and mixed-action) will be assessed in nonhuman primates. The stimulant effects of these compounds will be assessed by administering them systemically to squirrel monkeys trained on a stimulus termination task. The reinforcing effects will be assessed in separate groups of squirrel monkeys and rhesus monkeys that have been trained to self-administer cocaine. These data will allow us to determine the relative stimulant and reinforcing efficacy and potency of each combination. To determine drug effects on brain dopamine function, squirrel monkeys will undergo in vivo microdialysis procedures following drug administration, allowing us to determine how dopamine levels are altered by the administration of these drug combinations. PET imaging of DAT occupancy will be conducted in rhesus monkeys, allowing us to correlate DAT occupancy with the observed behavior and neurochemistry. Ex vivo binding assays will be conducted in rodents to determine the rate that these compounds bind to DAT. These data will further characterize the role of pharmacokinetics in the addictive properties of cocaine and provide critical information for the development of effective pharmacotherapies that are not, themselves, addictive. This research proposal will extend the candidate's research training in rodent behavioral pharmacology and neurochemistry to nonhuman primate behavioral pharmacology and neurochemistry. In addition, this research plan represents a new research direction for the applicant. The training experiences described will provide for the candidate's transition from a mentored scientist to an independent investigator. ? ? ? ?
