The experiments in this proposal are designed to investigate changes in normal brain function caused by cocaine. These experiments will focus on function in a circuit of structures including orbitofrontal cortex, basolateral amygdala, and nucleus accumbens. Experiments in rats and primates have shown that this circuit - largely conserved across species - is critical for goal-directed behavior or behavior that is guided by associations between cues and the incentive value of associated outcomes. It is now known that chronic intermittent exposure to cocaine - the stereotypical drug of abuse - alters molecular and structural properties of neurons in these brain areas. A growing set of reports indicates that these changes may cause fundamental changes in the normal functions that depend on these regions, changes that may be related to the complex behavioral changes that characterize addiction. However, animal models are necessary to determine whether changes observed in humans are caused by cocaine. To investigate this question, we propose to use data regarding the contribution of these areas to goal-directed behavior in normal rats as a background or model in which to investigate the effects of prior cocaine exposure. The proposed experiments have three components. The first component is a continued characterization of the involvement of these areas in goal-directed behavior in normal rats. The second component is an evaluation of the effects of chronic intermittent cocaine exposure on goal-directed behavior that is affected by lesions in these brain regions. The third component is a comparison of neural representations during goal-directed behavior in these brain regions in normal rats and rats that have received intermittent exposure to cocaine. This comparison will identify changes in neural activity or encoding that relate to the behavioral effects of prior cocaine exposure. These results will then serve as a platform for further investigations into whether and how changes that are identified in the normal operation of this brain circuit may be reversed by abstinence and/or treatment regimes. In addition, changes in function related to other human neuropsychiatric diseases involving these areas could also be pursued using this model.
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