Jesse T Kaye1,2,3, Gaylen E Fronk4, Aleksandra E Zgierska5, Maireni R Cruz5, David Rabago5, John J Curtin4. 1. Department of Psychology, University of Wisconsin, Madison, WI, USA. jtkaye@wisc.edu. 2. William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI, 53705, USA. jtkaye@wisc.edu. 3. Center for Tobacco Research and Intervention, University of Wisconsin School of Medicine and Public Health, 1930 Monroe St. #200, Madison, WI, 53711, USA. jtkaye@wisc.edu. 4. Department of Psychology, University of Wisconsin, Madison, WI, USA. 5. Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Abstract
RATIONALE: 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. OBJECTIVES: 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. METHODS: 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). RESULTS: 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. 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 noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.
RATIONALE: 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. OBJECTIVES: 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. METHODS: 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). RESULTS: 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. 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 noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.
Authors: Terry D Blumenthal; Bruce N Cuthbert; Diane L Filion; Steven Hackley; Ottmar V Lipp; Anton van Boxtel Journal: Psychophysiology Date: 2005-01 Impact factor: 4.016
Authors: Helen C Fox; George M Anderson; Keri Tuit; Julie Hansen; Anne Kimmerling; Kristen M Siedlarz; Peter T Morgan; Rajita Sinha Journal: Alcohol Clin Exp Res Date: 2011-09-15 Impact factor: 3.455
Authors: Boadie W Dunlop; Elisabeth B Binder; Dan Iosifescu; Sanjay J Mathew; Thomas C Neylan; Julius C Pape; Tania Carrillo-Roa; Charles Green; Becky Kinkead; Dimitri Grigoriadis; Barbara O Rothbaum; Charles B Nemeroff; Helen S Mayberg Journal: Biol Psychiatry Date: 2017-07-04 Impact factor: 13.382
Authors: Janice C Froehlich; Brett J Hausauer; David L Federoff; Stephen M Fischer; Dennis D Rasmussen Journal: Alcohol Clin Exp Res Date: 2013-06-03 Impact factor: 3.455