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.The development of effective medications to treat cocaine addiction will depend on a better understanding of cocaine neuropharmacology. The current project utilized positron emission tomography (PET) neuroimaging techniques in nonhuman primates as a noninvasive approach to investigate cocaine-induced functional changes in central nervous system activity. We have completed an extensive series of studies to compare the discriminative-stimulus, reinforcing and reinstatement effects of cocaine analogs with high affinity for binding to the dopamine transporter (DAT). Moreover, the behavioral pharmacology of the cocaine analogs was compared to their time course of uptake in brain using PET neuroimaging. Compounds were labeled with C-11, and PET imaging on a high-resolution MicroPET scanner was used to document the rate of uptake and clearance from brain in vivo in rhesus monkeys. All of the DAT inhibitors substituted for cocaine in drug-disrimination studies. Moreover, there was a significant correlation between the time course of discriminative-stimulus effects and the time to reach peak drug levels in brain measured by PET. There was also a significant correlation in the rank order of potency of the cocaine analogs in behavioral assays of drug-discrimination, drug self-administra tion and reinstatement effects. Hence the time course of uptake in brain predicts the behavioral pharmacology of DAT inhibitors in nonhuman primates. The results have important implication concerning the development of substitute agonist pharmacotherapies to treat stimulant abuse. Slow-onset, long-duration medications may enhance medication effectiveness and further limit the abuse potential of the medication.
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