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Description: Background: Norepinephrine plays a critical role in the stress response. Clarifying the psychopharmacological effects of norepinephrine manipulation on stress reactivity in humans has important implications for basic neuroscience and treatment of stress-related psychiatric disorders, such as posttraumatic stress disorder and alcohol use disorders. Preclinical research implicates the alpha-1 norepinephrine receptor in responses to stressors. The No Shock, Predictable Shock, Unpredictable Shock (NPU) task is a human laboratory paradigm that is well positioned to test cross-species neurobiological stress mechanisms and advance experimental therapeutic approaches to clinical trials testing novel treatments for psychiatric disorders. We hypothesized that acute administration of prazosin, an alpha-1 noradrenergic antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task. Methods: We conducted a double-blind, placebo-controlled, crossover randomized controlled trial in which sixty-four healthy adults (32 female) completed the NPU task at two visits (2mg prazosin vs. placebo). Results: A single acute dose of 2mg prazosin did not reduce stress reactivity in a healthy adult sample. Neither NPU startle potentiation nor self-reported anxiety was reduced by prazosin (vs. placebo) during unpredictable (vs. predictable) stressors. Conclusions: Further research is needed to determine whether this failure to translate preclinical neuroscience to human laboratory models is due to methodological factors (e.g., acute vs. chronic drug administration, brain penetration, study population) and/or suggests limited clinical utility of alpha-1 noradrenergic antagonists for treating stress-related psychiatric disorders.