Cocaine, Impulsivity, and PHNO Across Species

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The main goal of this PET imaging section of the P20 proposal (Project 2) is to better understand the neural mechanisms associated with the two major types of impulsive behavior (impulsive choice and impulsive response) as related to drug abuse, by assessing the neurochemical and behavioral differences in cocaine dependent (CD) subjects as compared to healthy control (HC) subjects. We propose to compare the binding potential of [11C]PHN0, a potent dopamine D2/D3 PET agonist ligand, in ventral and dorsal striatum of HC and CD (Specific Aim 1), and then correlate the binding potential with the event-related BOLD activity measured by fMRI (Project 1) during a task assessing impulsive choice and during a task assessing impulsive response (Specific Aim 2). We further propose to conduct PET imaging in rats and non-human primates before and after cocaine exposure and correlate the results on the dopamine D2/D3 availability with impulsivity measures using the same cognitive/behavior tasks. This is the first study specifically designed to characterize impulsivity across all three species, both behaviorally and neurochemically, and to investigate the relationship of impulsivity to cocaine addiction. The proposed translafional research will provide synergisfic informafion by linking the clinical and preclinical findings to address a major gap in our understanding of the factors that influence addiction liability or vulnerability to the effects of drugs, the neurobiological alterations that may lead to abuse and addicfion, and how drugs of abuse may affect brain systems and processes that change over time after exposure to drugs. By employing neuroimaging technology (Project 2) paired with sophisficated functional and behavioral measurement paradigms (Project 1 & 3), and by integrating viral-mediated gene expression study (Project 4), we can begin to better understand the alterafion induced by cocaine at mulfiple levels, including the molecular genefic, neural and behavioral levels. Thus, the proposed study has significant potenfial to yield results that can be inform treatment development for cocaine addiction in humans.