Chronic unpredictable stress (CUS) impairs cognitive flexibility in rats, particularly when faced with additional mild acute stress (AS). We tested the hypothesis that this impairment is associated with alterations in dopamine activity in the dorsal striatum driven by corticotropin-releasing-factor receptor type 1 (CRFR1) in the substantia nigra pars compacta (SNpc). In experiment 1, rats received CUS or handling for 14 days, before learning two action-outcome associations (lever presses and

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... d rewards). Learning was assessed using outcome devaluation. Cognitive flexibility was then assessed by reversing the outcome identities followed by a second outcome devaluation test, with half of the rats in each group receiving AS prior to reversal training. Dopamine and its metabolite were quantified in the dorsal striatum and CRFR1 mRNA was quantified in the SNpc. Increased dopaminergic activity in the left dorsal striatum and CRFR1 expression in the left SNpc were associated with resilience to AS in naive rats but with impairment in CUS+AS rats, suggesting a transition in hemispheric control from left to right as a protective mechanism following CUS. This suggestion was tested in experiment 2, where SNpc CRFR1 was blocked unilaterally prior to AS and reversal training. Blocking CRFR1 in the left medial SNpc impaired cognitive flexibility following AS in naive rats but restored it in CUS rats. Blocking CRFR1 in the left, but not right, lateral SNpc also impaired cognitive flexibility following AS in naive rats but had no effect in CUS rats.