Acute prazosin administration does not reduce stressor reactivity in healthy adults
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 norepinephrine alpha-1 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, a noradrenergic alpha-1 antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task.
We conducted a double-blind, placebo-controlled, crossover randomized controlled trial in which 64 healthy adults (32 female) completed the NPU task at two visits (2 mg prazosin vs. placebo).
A single acute dose of 2 mg 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.
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 noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.
KeywordsStress Prazosin Noradrenaline Startle response Startle potentiation Posttraumatic stress disorder Alcohol use disorder
We thank Heather M. Williams for assistance with data collection and the University of Wisconsin (UW) Clinical Research Unit and UW Pharmaceutical Research Center for study support. Portions of this research have previously been presented at the annual conferences of the Society for Psychophysiology Research. This manuscript has been published on the preprint server PsyArXiv.
Research reported in this publication was supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) under award numbers R01 AA024388 (J Curtin) and F31 AA022845 (J Kaye), NIH National Center for Advancing Translational Science under the Clinical and Translational Science Award number UL1TR000427 to the UW Institute for Clinical and Translational Research, and by intramural research awards from the UW Office of the Vice Chancellor for Research and Graduate Education (J Curtin).
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Conflict of interest
The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, VA, or UW. The authors have no biomedical financial interests or potential conflicts of interest.
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