Skip to main content

Acute prazosin administration does not reduce stressor reactivity in healthy adults

Psychopharmacology volume 236, pages 3371–3382 (2019)Cite this article

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3

Notes

  1. We preregistered a sequential recruitment plan to enroll an equal number of participants with AUD in early recover if we confirmed our hypothesis that prazosin reduced stress reactivity to unpredictable (vs. predictable) stressors in health adults (https://clinicaltrials.gov/ct2/show/NCT02966340).

  2. The University of Iowa Pharmaceuticals prepared and over-encapsulated study drug and matching placebos. The University of Wisconsin Pharmaceutical Research Center implemented and maintained the randomization and blind. At visit 1, participants were randomized 1:1 to Drug Order (A: visit 1 prazosin and visit 2 placebo; B: visit 1 placebo and visit 2 prazosin) and NPU Task Order (four condition and startle probe counterbalancing orders), stratified by Sex.

  3. In accordance with our pre-registration, we excluded and replaced two participants with general startle reactivity at their first study visit of < 5 μV (non-responders).

  4. We analyze raw startle potentiation consistent with our preregistered analysis plan and numerous previous studies with this and related tasks (Moberg and Curtin 2009; Bradford et al. 2013, 2014; Kaye et al. 2016; Moberg et al. 2017). We report analyses of startle response during the no-shock blocks to confirm that observed effects result from shock threat rather than control condition (no-shock block) differences (see footnote 6 and 8). We do not standardize startle potentiation as it yields lower internal consistency and temporal stability than raw startle potentiation in the NPU task (Bradford et al. 2015; Kaye et al. 2016). Consistent with our previous studies, we also limit analyses to the cue period in predictable and unpredictable blocks to control for (i.e., match) the attentional demands associated with the visual foreground across these blocks (Lang et al. 1990).

  5. We collected a battery of other measures that were available to be used as either covariates or moderators in the analysis of the primary and secondary dependent variables (see Supplement). We utilize covariates to increase power to detect the focal effect in our analytic models. We preregistered to select covariates if we confirmed that the specific covariate (e.g., general startle reactivity, drug order, intolerance of uncertainty) significantly predicted the test of the primary hypothesis (i.e., two-way interaction between drug and NPU task condition). Any categorical between-subject factors were coded as unit-weighted, centered, orthogonal regressors (e.g., sex: male = − 0.5, female = 0.5). Any continuous/quantitative individual difference covariates were mean-centered. We conducted analyses separately for each dependent variable (e.g., startle potentiation, self-reported fear/anxiety potentiation) with only one covariate in the model at a time to determine covariate selection. We only used the covariate if it was a significant predictor of the drug X NPU condition interaction for each dependent variable separately (e.g., startle potentiation or self-reported fear/anxiety potentiation).

  6. We did not include any covariates in models predicting the two-way interaction on startle potentiation (primary outcome) or self-reported anxiety (secondary outcome) as none met our preregistered decision threshold. We did not identify or remove any model outliers (i.e., Bonferroni-corrected studentized residuals, p < .05).

  7. There was not a significant effect of drug on startle response only during the No Shock condition, ηp2 = .039, b = 4.2 μV, t(61) = 1.57, p = .121, suggesting that the main effect of prazosin on startle potentiation (i.e., shock cues minus no-shock cues) was not driven by a reduction in startle during No Shock.

  8. In the unadjusted model, there was not a significant main effect of drug on overall startle potentiation, ηp2 = .107, b = − 6.8 μV, t(63) = − 1.97, p = .053, with no covariates included or outliers removed.

  9. We removed one model outlier, but there was still not a significant main effect of drug on overall self-reported anxiety/fear, ηp2 = .008, b = 0.09, t(63) = 0.70, p = .484, with no outliers removed. We did not include any covariates in either model predicting the drug main effect on self-reported anxiety as none met our preregistered decision threshold. We also confirmed that was not a significant effect of drug on startle response during the No Shock condition, ηp2 = .013, b = 0.06, t(62) = 0.89, p = 0.375.

  10. Previous literature suggests that prazosin’s peak effects on peripheral physiology and plasma concentration occur 1–4 h post-administration (Jaillon 1980). Unfortunately, there is limited research in humans to confirm the time course of effects in the brain (but see Rutland et al. 1980). Although prazosin is still widely used in rodent behavioral neuroscience research today to study the central nervous system, human studies have primarily examined peripheral physiology as prazosin was originally developed as an antihypertensive agent. Indeed, very few studies have examined basic acute effects of prazosin in humans since the 1970s.

  11. Considerable preclinical research supports our study hypothesis that acute prazosin would selectively reduce startle potentiation during unpredictable (relative to predictable) shock. However, the most direct translational design of our current study in humans (i.e., acute prazosin effects on startle potentiation to unpredictable vs predictable shock) has not been performed in rodent models to date. We believe reverse-translation of our current study design in rodents, using parallel pharmacological manipulation (acute prazosin), stressor manipulation (unpredictable vs. predictable shock), and measurement (startle potentiation) is essential to clarify convergent or divergent results across species. Furthermore, additional psychopharmacology studies in both human and rodent models should address differences in acute vs chronic prazosin administration. Only recently have preclinical labs begun to examine the effects of chronic prazosin on relevant anxiety-like behaviors and alcohol use/seeking behaviors (Froehlich et al. 2013; Skelly and Weiner 2014; Rasmussen et al. 2017). However, no studies have examined chronic prazosin administration effects on startle response as the primary outcome measure.

References

Download references

Acknowledgements

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.

Funding

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).

Author information

Authors and Affiliations

  1. Department of Psychology, University of Wisconsin, Madison, WI, USA

    Jesse T Kaye, Gaylen E Fronk & John J Curtin

  2. William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI, 53705, USA

    Jesse T Kaye

  3. Center for Tobacco Research and Intervention, University of Wisconsin School of Medicine and Public Health, 1930 Monroe St. #200, Madison, WI, 53711, USA

    Jesse T Kaye

  4. Department of Family Medicine and Community Health, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Aleksandra E Zgierska, Maireni R Cruz & David Rabago

Authors
  1. Jesse T Kaye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gaylen E Fronk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aleksandra E Zgierska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maireni R Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Rabago
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John J Curtin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jesse T Kaye.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 78 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kaye, J.T., Fronk, G.E., Zgierska, A.E. et al. Acute prazosin administration does not reduce stressor reactivity in healthy adults. Psychopharmacology 236, 3371–3382 (2019). https://doi.org/10.1007/s00213-019-05297-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-019-05297-x

Keywords

  • Stress
  • Prazosin
  • Noradrenaline
  • Startle response
  • Startle potentiation
  • Posttraumatic stress disorder
  • Alcohol use disorder