Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD Daphna Fenchel a , Yechiel Levkovitz a,n , Ella Vainer b , Zeev Kaplan c , Joseph Zohar d , Hagit Cohen c a Beer-Yaakov Mental Health Center, Ministry of Health, Sackler Faculty of Medicine, Tel Aviv University, Beer-Yaakov, Israel b Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel c Beer-Sheva Mental Health Center, Ministry of Health, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel d Division of Psychiatry, The Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel Received 24 November 2014; received in revised form 8 February 2015; accepted 20 February 2015 KEYWORDS Post-traumatic stress disorder; HPA-axis; HPG-axis; Androgen receptor; Estrogen receptor α; Testosterone Abstract The hypothalamic–pituitary–adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic–pituitary–gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed www.elsevier.com/locate/euroneuro http://dx.doi.org/10.1016/j.euroneuro.2015.02.004 0924-977X/& 2015 Elsevier B.V. and ECNP. All rights reserved. n Corresponding author. Tel.: + 972 8 9258248; fax: + 972 89258354. E-mail address: yeheal@post.tau.ac.il (Y. Levkovitz). European Neuropsychopharmacology (2015) 25, 944–957