Common and dissociable effects of oxytocin and lorazepam on the neurocircuitry of fear

Kreuder A, Scheele D, Schultz J, Hennig J, Marsh N, Dellert T, Ettinger U, Philipsen A, Babasiz M, Herscheid A, Remmersmann L, Stirnberg R, Stöcker T, Hurlemann R

Abstract

Benzodiazepines (BZDs) represent the gold standard of anxiolytic pharmacotherapy; however, their clinical benefit is limited by side effects and addictive potential. Consequently, there is an urgent need to develop novel and safe anxiolytics. The peptide hormone oxytocin (OXT) exhibits anxiolytic-like properties in animals and humans, but whether OXT and BZDs share similar effects on the neural circuitry of fear is unclear. Therefore, the rationale of this ultra-high-field functional MRI (fMRI) study was to test OXT against the clinical comparator lorazepam (LZP) with regard to their neuromodulatory effects on local and network responses to fear-related stimuli. One hundred twenty-eight healthy male participants volunteered in this randomized double-blind, placebo-controlled, between-group study. Before scanning using an emotional face-matching paradigm, participants were randomly administered a single dose of OXT (24 IU), LZP (1 mg), or placebo. On the behavioral level, LZP, but not OXT, caused mild sedation, as evidenced by a 19\% increase in reaction times. On the neural level, both OXT and LZP inhibited responses to fearful faces vs. neutral faces within the centromedial amygdala (cmA). In contrast, they had different effects on intra-amygdalar connectivity; OXT strengthened the coupling between the cmA and basolateral amygdala, whereas LZP increased the interplay between the cmA and superficial amygdala. Furthermore, OXT, but not LZP, enhanced the coupling between the cmA and the precuneus and dorsomedial prefrontal cortex. These data implicate inhibition of the cmA as a common denominator of anxiolytic action, with only OXT inducing large-scale connectivity changes of potential therapeutic relevance. Author Information Ann-Kathrin Kreudera, Dirk Scheelea,b, Johannes Schultzc, Juergen Hennigd, Nina Marshb, Torge Dellerte, Ulrich Ettingerf, Alexandra Philipseng, Mari Babasiza, Angela Herscheida, Laura Remmersmanna, Ruediger Stirnbergh, Tony Stöckerh,i, and René Hurlemanna,b,j,1aDivision of Medical Psychology, Department of Psychiatry and Psychotherapy, University Hospital Bonn, 53105 Bonn, Germany;bDepartment of Psychiatry, School of Medicine & Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany;cCenter for Economics and Neuroscience, University of Bonn, 53113 Bonn, Germany;dDivision of Personality Psychology and Individual Differences, University of Giessen, 35390 Giessen, Germany;eInstitute of Medical Psychology and Systems Neuroscience, University of Muenster, 48149 Muenster, Germany;fDepartment of Psychology, University of Bonn, 53113 Bonn, Germany;gDepartment of Psychiatry and Psychotherapy, University Hospital Bonn, 53105 Bonn, Germany;hDivision of MR Physics, German Center for Neurodegenerative Diseases, 53175 Bonn, Germany;iDepartment of Physics and Astronomy, University of Bonn, 53113 Bonn, Germany;jResearch Center Neurosensory Science, University of Oldenburg, 26129 Oldenburg, GermanyEdited by Bruce S. McEwen, Rockefeller University, New York, NY, and approved March 31, 2020 (received for review November 15, 2019) Footnotes↵1To whom correspondence may be addressed. Email: renehurlemann@icloud.com.Author contributions: A.-K.K., D.S., J.S., and R.H. designed research; A.-K.K., N.M., T.D., M.B., A.H., L.R., and R.H. performed research; R.S. and T.S. contributed new reagents/analytic tools; A.-K.K., D.S., J.S., and R.H. analyzed data; and A.-K.K., D.S., J.S., J.H., N.M., T.D., U.E., A.P., M.B., A.H., L.R., R.S., T.S., and R.H. wrote the paper.The authors declare no competing interest.This article is a PNAS Direct Submission.This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1920147117/-/DCSupplemental.