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 (1 and {beta}). 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 (1, 2, and {beta}) activity during an active avoidance and reward seeking task in male and female rats. We found modulating noradrenergic activity on low affinity 1 and {beta} receptors but not 2 receptors disrupted reinforcement behavior. Increased 1, but to a greater extent {beta} 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 1 and {beta} 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. SIGNIFICANCE STATEMENTWhile we know norepinephrine is a fundamental component of the acute stress response, it is unknown how that stress related noradrenergic receptor activity impacts reinforcement behavior, both positive and negative. Here, we show that stress related norepinephrine signaling is differentially involved in positive and negative reinforcement behavior and directly shifts behavioral strategies from active avoidance to passive coping. These results identify that noradrenergic receptor activity can mediate the transition from adaptive to maladaptive behaviors during stress, especially in the context of negative reinforcement.