B1 noradrenergic blockade in early withdrawal to reduce cocaine induced behavioral flexibility deficit

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PROJECT SUMMARY Balancing habitual and flexible strategies for navigating the environment is necessary for behavior that is both cognitively efficient yet adaptive to change, and perturbations that disrupt this balance can result in significant behavioral impairments. For example, patients with substance abuse disorders often have difficulty altering their behavior to respond to changing outcomes, leading to poor decision-making. In the rat, a history of cocaine impairs the ability to adjust behavior away from reward-predictive cues following reward devaluation, a canonical measure of flexible behavior (i.e., cocaine leads to inflexible behavior). Interestingly, different striatal substrates underlie flexible, goal-directed behaviors (nucleus accumbens, NAc) and inflexible, habitual behaviors (dorsal lateral striatum, DLS), and proper balance between the NAc and DLS and their associated networks is critical for adaptive (flexible) but efficient (habitual) behavior. The parent award for this diversity supplement examines how a history of cocaine tips that balance and alters the neural network signaling that drives flexible and inflexible strategies. Balancing these subcortical networks requires cortical input. Specifically, to determine how distinct mPFC subregions (prelimbic cortex, PrL; and infralimbic cortex, IL) are differentially involved in flexible and inflexible strategies, respectively. Here, we will focus on elucidating how a history of cocaine leads to inflexible behavior and aberrant PrL and IL neural activity. We propose that early stress during withdrawal contributes to deficits in behavioral flexibility induced by cocaine self- administration. Corticosterone treatment is sufficient to shift behavior towards inflexible strategies, similar to what we have reported with a history of cocaine. Since β1 antagonism can reduce early cocaine withdrawal symptoms such as elevated anxiety and corticosterone, we hypothesize that this treatment will restore cocaine induced deficits in flexible behavior. This project will allow for the candidate to learn new techniques (surgeries, self-administration, in vivo electrophysiological analysis) and prepare for continuing my research career by applying to graduate school. Understanding the neural circuitry underlying inflexible behavior how neural encoding in these regions is altered by drug use will provide critical insight into new and more selective targets for therapeutic intervention for patients with substance abuse disorders.