Beyond the HPA-axis: the role of the gonadal steroid hormone receptors in modulating stress related responses in an animal model of PTSD

Abstract

Rationale : The activation of the neuroendocrine systems is a basic response to environmental perturbations, which threaten homeostasis. The HPA-axis is one of the primary effector systems, which functions to minimize deviations from the homeostatic state and help to return equilibrium following a disturbance. It has been well established that products of the HPA-axis can directly inhibit the hypothalamo-pituitary-gonadal (HPG)-axis. Consequently, following chronic stressors reproduction is impaired. Method : Animals were exposed to predator scent stress for 15 min. Behaviors were assessed with the elevated plus-maze and acoustic startle response tests, 7 days later. Trauma-cue response, circulating corticosterone and testosterone, and localized brain expression of androgen receptor (AR) and estrogen receptors were subsequently assessed. All data were analyzed in relation to individual behavior patterns. The behavioral effects of testosterone agonist, testosterone receptor antagonist (flutamide), or vehicle-administered systemic one hour before and 7 days after PSS-exposure were evaluated in the same manner. Results : Animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR in the hippocampus compared to animals whose behavior was minimally (MBR) or partially (PBR) disrupted and to un-exposed controls.One-hour pre-exposure treatment with testosterone significantly increased prevalence rates of EBR and increased trauma-cue freezing responses, compared to vehicle controls. In contrast, immediate pre-exposure treatment with flutamide significantly reduced prevalence rates of extreme responders and reduced trauma-cue freezing responses compared to vehicle and testosterone treatments. Moreover, treatment with testosterone 7 days post exposure significantly reduced prevalence rates of extreme responders and reduced trauma-cue freezing responses compared to vehicle and testosterone treatments. Conclusions : The gonadal steroid hormones are actively 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.

Keywords

• PTSD
• animal models
• gonadal steroid hormones
• stress response
• HPA Axis