This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Currently, there is no effective medication for treating cocaine addiction. A better understanding of how 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 attributed primarily to its effects at the dopamine transporter (DAT). However, not all DAT inhibitors are equally reinforcing. It is important to examine the properties involved in the effects of these compounds. In the present research, the reinforcing effectiveness of several monoamine transporter inhibitors (DAT-selective and mixed-action) is assessed in nonhuman primates. The stimulant effects of these compounds are assessed by administering them systemically to squirrel monkeys trained on a stimulus-termination task. The reinforcing effects are assessed in separate groups of squirrel monkeys trained to self-administer cocaine. These data will enable us to determine the relative stimulant and reinforcing efficacy and potency of each combination. To determine drug effects on brain dopamine function, squirrel monkeys undergo in vivo microdialysis procedures following drug administration. PET imaging of the uptake of Radiolabeled monoamine transporter inhibitors is conducted in rhesus monkeys to correlate drug levels in brain with observed behavior and neurochemistry. The present data showed that the time to peak drug levels in brain were very highly correlated with the time to peak increases in brain dopamine. In addition, the data showed a trend for compounds with a shorter duration of action or DAT selectivity to produce significant behavioral-stimulant and reinforcing effects. These data 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.
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