Decision-Making Dysfunction and Chronic Cocaine

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Although many people use drugs of abuse occasionally, few people develop a drug addiction. The likelihood that an individual transitions from occasional to compulsive patterns of drug use may depend upon aberrant pre-existing decision-making processes. We were among the first to argue that prefrontal dysfunction mediates top-down behavioral control in addiction, a perspective that is now widely recognized, and we have provided supporting evidence that decision-making deficits, incentive motivation and habits, and neurobehavioral plasticity are impacted in animal models of addiction. Nonetheless, a more mechanistic, circuit-driven approach is needed to dissect the precise relationship between individual differences in decision-making dysfunction and vulnerability to addiction from the consequence of chronic drug exposure. We will use cutting-edge viral tools to characterize the neurobiological relationship between aberrant decision-making strategies in rats on the development and persistence of addiction-like behavior. Here we focus on the role of orbitofrontal cortex (OFC) projections to distinct subcortical targets (OFC-to-amygdala and OFC-to-nucleus accumbens) in decision- making processes. Novel tasks will be used that assess the ability of rats to adapt behavior to changing reinforcement contingencies or make choices based on abstract representations of action-reinforcement contingencies. We hypothesize that by using highly-translational behavioral tasks that are dependent upon the OFC and computational models to better characterize decision-making processes, we will isolate the OFC- dependent circuitry and mechanisms that underlie addiction vulnerability. In Aim 1, we will identify precise decision-making processes that predict vulnerability to cocaine-taking behaviors by combining retro-fitted behavioral tasks with sophisticated computational analyses. In Aim 2, we will characterize the role of specific OFC circuits in decision-making behaviors that predict vulnerability to cocaine-taking behavior using a novel circuit-specific, retroviral ablation approach to identify and remove specific top-down OFC circuits. Finally, in Aim 3, we will investigate the role of plasticity mediated by neural cell adhesion molecule (NCAM) and its proplastic modified form, polysialylated NCAM (PSA-NCAM) within OFC circuits, in decision-making processes that predict vulnerability to cocaine-taking behaviors using viral tools. Overall, results from this work should provide an innovative perspective on the role of selective loss of top-down, OFC–subcortical control on decision-making processes and vulnerability to addiction. These studies have the potential to inspire the development of novel therapeutic strategies, open new areas of investigation for biological psychiatry and neuroscience, and produce highly translational results for human addiction.