Low affinity noradrenergic signaling promotes passive coping during reinforcement behavior

During stress and in many psychiatric disorders the ability to appropriately recognize and respond to cues to avoid negative outcomes (e.g., injury) and achieve positive outcomes (e.g., food) is disrupted. A critical component of the stress response is increased noradrenergic tone, acting on lower affinity noradrenergic receptors (α1 and β). Noradrenergic signaling is essential for cue-driven behavior, yet how noradrenergic components of the stress response impacts positive and negative reinforcement behavior is still unknown. We manipulated noradrenergic receptor (α1, α2, and β) activity during an active avoidance and reward seeking task in male and female rats. We found modulating noradrenergic activity on low affinity α1 and β receptors but not α2 receptors disrupted reinforcement behavior. Increased α1, but to a greater extent β receptor activity shifted negative reinforcement behavior away from active avoidance and towards passive coping by increasing decision thresholds. We also found sex differences in the impact of α1 and β noradrenergic activity on reward seeking. Overall, stress related noradrenergic signaling deceased active avoidance behavior by shifting strategy towards passive coping. Reward seeking was more robust in females but not males. Collectively these results identify sex differences in noradrenergic dependent stress response behaviors and highlight low affinity adrenoreceptors as relevant therapeutic targets to mitigate the impact of stress on goal-directed behavior.