title: Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD.
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 animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.
authors.affiliation: Beer-Yaakov Mental Health Center, Ministry of Health, Sackler Faculty of Medicine, Tel Aviv University, Beer-Yaakov, Israel.
authors.forename: Daphna
authors.initials: D
authors.lastname: Fenchel
authors.affiliation: Beer-Yaakov Mental Health Center, Ministry of Health, Sackler Faculty of Medicine, Tel Aviv University, Beer-Yaakov, Israel. Electronic address: yeheal@post.tau.ac.il.
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Levkovitz
authors.affiliation: Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Vainer
authors.affiliation: 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.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Kaplan
authors.affiliation: Division of Psychiatry, The Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Ramat-Gan, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zohar
authors.affiliation: 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.
authors.forename: Hagit
authors.initials: H
authors.lastname: Cohen
mesh_terms: D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016009:Chi-Square Distribution; D003345:Corticosterone / Q000097:blood*; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D013216:Reflex, Startle; D013313:Stress Disorders, Post-Traumatic / Q000209:etiology / Q000473:pathology*; D013315:Stress, Psychological / Q000150:complications; D013739:Testosterone / Q000097:blood* / Q000494:pharmacology
chemical_list: D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D013739:Testosterone; D003345:Corticosterone
keywords: Androgen receptor; Estrogen receptor α; HPA-axis; HPG-axis; Post-traumatic stress disorder; Testosterone