This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 1) The Neural Correlates for Shifting the neutral Nature of Drug Stimuli to be the Predictors of Drug Rewards in the Human Brain. Seventeen human cocaine users and eighteen control human subjects successfully participated in the cocaine-cue elicited cocaine craving study by using functional MRI (fMRI) method. The content-specificity and population specificity indicated that cocaine-cue films successfully elicited subjective craving and activated two groups of the addiction-encoded neural correlates. One group is associated with the psychological arousal, episodic memory retrieval, attention, and behavioral planning in the prefrontal (such as in Brodmann Area 10), temporal and occipital cortex. The other group is positively correlated with the cocaine craving rating, such as in the subcollosal cortex (SCC) and the anterior medial orbitofrontal cortex (amOFC). Our results demonstrate that the neural correlates in the SCC have shifted the environmental drug stimuli from their neutral nature to the predictors of cocaine rewards. The neurobiological mechanisms responsible for such a shift may be the completion of a functional establishment in SCC from an unconditioned reward detector to conditioned reward predictor due to the over-learning of the cue-drug pairing, a key neurobiological characteristic of the addiction. It is suggested that the activated signal in the amOFC region represent the motivational potential and the craving is the manifestation of this motivational potential that drives the drug seeking and taking behavior. 2) Neural Responses to Acute Cocaine Administration in the Human Brain Detected by fMRI. Understanding the neurobiological processes responsible for the altered behaviors that drives drug-taking behavior is a central challenge in addiction research. With an improved functional MRI (fMRI) method for detecting a blood oxygenation level dependent (BOLD) contrast, we report that acute cocaine administration to human cocaine users concurrently activates the mesolimbic and mesocortical dopaminergic projections, which in turn may gate the hierarchical brain networks in anterior prefrontal cortex (aPFC) of the Brodmann Area 10 (BA10) and orbitofrontal cortex (OFC) that mediate associative learning, motivation and memory. It is suggested that the negative BOLD responses in the mesocorticolimbic dopaminergic circuitry represent the bottom-up reward encoding processes essential for drug-induced acquisition of addictive behavior, whereas the positive BOLD signal in the BA10 and OFC regions represents the bottom-up addiction encoding processes that repeated cocaine use could repeatedly initiate to strengthen this learned association into a state of addiction.
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